Here are the studies that match your search criteria. If you are interested in participating, please reach out to the contact listed for the study. If no contact is listed, contact us and we'll help you find the right person.
Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy
This phase III trial studies whether inotuzumab ozogamicin added to post-induction
chemotherapy for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves
outcomes. This trial also studies the outcomes of patients with mixed phenotype acute
leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without
inotuzumab ozogamicin. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab,
linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells in
a targeted way and delivers calicheamicin to kill them. Other drugs used in the chemotherapy
regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin,
methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and
pegaspargase or calaspargase pegol work in different ways to stop the growth of cancer cells,
either by killing the cells, by stopping them from dividing, or by stopping them from
spreading. This trial will also study the outcomes of patients with mixed phenotype acute
leukemia (MPAL) and disseminated B lymphoblastic lymphoma (B-LLy) when treated with high-risk
ALL chemotherapy.
The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard
of care chemotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic
Leukemia (HR B-ALL). The first part of the study includes the first two phases of therapy:
Induction and Consolidation. This part will collect information on the leukemia, as well as
the effects of the initial treatment, in order to classify patients into post-consolidation
treatment groups. On the second part of this study, patients will receive the remainder of
the chemotherapy cycles (interim maintenance I, delayed intensification, interim maintenance
II, maintenance), with some patients randomized to receive inotuzumab. Other aims of this
study include investigating whether treating both males and females with the same duration of
chemotherapy maintains outcomes for males who have previously been treated for an additional
year compared to girls, as well as to evaluate the best ways to help patients adhere to oral
chemotherapy regimens. Finally, this study will be the first to track the outcomes of
subjects with disseminated B-cell Lymphoblastic Leukemia (B-LLy) or Mixed Phenotype Acute
Leukemia (MPAL) when treated with B-ALL chemotherapy.
• B-ALL and MPAL patients must be enrolled on APEC14B1 and consented to eligibility
studies (Part A) prior to treatment and enrollment on AALL1732. Note that central
confirmation of MPAL diagnosis must occur within 22 business days after enrollment for
MPAL patients. If not performed within this time frame, patients will be taken off
protocol.
• APEC14B1 is not a requirement for B-LLy patients but for institutional compliance
every patient should be offered participation in APEC14B1. B-LLy patients may directly
enroll on AALL1732.
• Patients must be > 365 days and < 25 years of age
• White blood cell count (WBC) criteria for patients with B-ALL (within 7 days prior to
the start of protocol-directed systemic therapy):
• Age 1-9.99 years: WBC >= 50,000/uL
• Age 10-24.99 years: Any WBC
• Age 1-9.99 years: WBC < 50,000/uL with:
• Testicular leukemia
• CNS leukemia (CNS3)
• Steroid pretreatment.
• White blood cell count (WBC) criteria for patients with MPAL (within 7 days prior to
the start of protocol-directed systemic therapy):
• Age 1-24.99 years: any WBC.
• Patient has newly diagnosed B-ALL or MPAL (by World Health Organization [WHO] 2016
criteria) with >= 25% blasts on a bone marrow (BM) aspirate;
• OR If a BM aspirate is not obtained or is not diagnostic of acute leukemia, the
diagnosis can be established by a pathologic diagnosis of acute leukemia on a BM
biopsy;
• OR A complete blood count (CBC) documenting the presence of at least 1,000/uL
circulating leukemic cells if a bone marrow aspirate or biopsy cannot be
performed.
• Patient has newly diagnosed B-LLy Murphy stages III or IV.
• Patient has newly diagnosed B-LLy Murphy stages I or II with steroid pretreatment.
• Note: For B-LLy patients with tissue available for flow cytometry, the criterion for
diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e.,
paraffin blocks), the methodology and criteria for immunophenotypic analysis to
establish the diagnosis of B-LLy defined by the submitting institution will be
accepted.
• All patients and/or their parents or legal guardians must sign a written informed
consent.
• All institutional, Food and Drug Administration (FDA), and NCI requirements for human
studies must be met.
Exclusion Criteria:
• Patients with Down syndrome are not eligible (patients with Down syndrome and B-ALL
are eligible for AALL1731, regardless of NCI risk group).
• With the exception of steroid pretreatment or the administration of intrathecal
cytarabine, patients must not have received any prior cytotoxic chemotherapy for the
current diagnosis of B-ALL, MPAL, or B-LLy or for any cancer diagnosed prior to
initiation of protocol therapy on AALL1732.
• Patients who have received > 72 hours of hydroxyurea within one week prior to start of
systemic protocol therapy.
• Patients with B-ALL or MPAL who do not have sufficient diagnostic bone marrow
submitted for APEC14B1 testing and who do not have a peripheral blood sample submitted
containing > 1,000/uL circulating leukemia cells.
• Patients with acute undifferentiated leukemia (AUL) are not eligible.
• For Murphy stage III/IV B-LLy patients, or stage I/II patients with steroid
pretreatment, the following additional exclusion criteria apply:
• T-lymphoblastic lymphoma.
• Morphologically unclassifiable lymphoma.
• Absence of both B-cell and T-cell phenotype markers in a case submitted as
lymphoblastic lymphoma.
• Patients with known Charcot-Marie-Tooth disease.
• Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL,
regardless of blast immunophenotype.
• Patients requiring radiation at diagnosis.
• Female patients who are pregnant, since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required for female
patients of childbearing potential.
• Lactating women who plan to breastfeed their infants while on study and for 2 months
after the last dose of inotuzumab ozogamicin.
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of study participation. For those
patients randomized to inotuzumab ozogamicin, there is a minimum of 8 months after the
last dose of inotuzumab ozogamicin for females and 5 months after the last dose of
inotuzumab ozogamicin for males.
B Acute Lymphoblastic Leukemia, Central Nervous System Leukemia, Testicular Leukemia, Mixed Phenotype Acute Leukemia, B Lymphoblastic Lymphoma, Leukemia, Other
A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and Low-Grade Glioma
This phase III trial studies if selumetinib works just as well as the standard treatment with
carboplatin/vincristine (CV) for subjects with NF1-associated low grade glioma (LGG), and to
see if selumetinib is better than CV in improving vision in subjects with LGG of the optic
pathway (vision nerves). Selumetinib is a drug that works by blocking some enzymes that
low-grade glioma tumor cells need for their growth. This results in killing tumor cells.
Drugs used as chemotherapy, such as carboplatin and vincristine, work in different ways to
stop the growth of tumor cells, either by killing the cells, by stopping them from dividing,
or by stopping them from spreading. It is not yet known whether selumetinib works better in
treating patients with NF1-associated low-grade glioma compared to standard therapy with
carboplatin and vincristine.
• Patients must be >= 2 years and =< 21 years at the time of enrollment
• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
• Patients must have neurofibromatosis type 1 (NF1) based on clinical criteria and/or
germline genetic testing
• Patients must be newly diagnosed or have previously diagnosed NF-1 associated LGG that
has not been treated with any modality other than surgery
• For patients with optic pathway gliomas (OPGs):
• Newly-diagnosed patients with OPG are eligible if there are neurologic symptoms
(including visual dysfunction, as defined below) or other exam findings
associated with the tumor
• Previously-diagnosed patients with OPG are eligible if they have new or worsening
neurologic symptoms (including visual dysfunction, as defined below) or have
tumor growth
• For both newly-diagnosed and previously-diagnosed OPG, the patient may be
eligible, irrespective of whether there has been tumor growth or other
neurological symptoms or worsening, if they meet at least one of the following
visual criteria:
• Visual worsening, defined as worsening of visual acuity (VA) or visual
fields (VF) documented within the past year (by examination or history); OR
• Significant visual dysfunction (defined as VA worse than normal for age by
0.6 logMAR [20/80, 6/24, or 2.5/10] or more in one or both eyes)
• For patients with LGG in other locations (i.e., not OPGs):
• Newly-diagnosed patients with LGG are eligible if there are neurologic symptoms
or other exam findings associated with the tumor
• NOTE: Newly-diagnosed patients with LGG without associated neurologic
symptoms or exam findings are not eligible
• Previously-diagnosed patients with LGG are eligible if they have new or worsening
neurologic symptoms or have tumor growth
• Although not required, if a biopsy/tumor resection is performed, eligible histologies
will include all tumors considered LGG or low-grade astrocytoma (World Health
Organization [WHO] grade I and II) by 5th edition WHO classification of central
nervous system (CNS) tumors with the exception of subependymal giant cell astrocytoma
• Patients must have two-dimensional measurable tumor >= 1 cm^2
• Patients with metastatic disease or multiple independent primary LGGs are allowed on
study
• Creatinine clearance or radioisotope glomerular filtration Rate (GFR) >= 70
mL/min/1.73 m^2 OR a serum creatinine based on age/gender (within 7 days prior to
enrollment) as follows:
• Age; maximum serum creatinine (mg/dL)
• 2 to < 6 years; 0.8 (male) and 0.8 (female)
• 6 to < 10 years; 1 (male) and 1 (female)
• 10 to < 13 years; 1.2 (male) and 1.2 (female)
• 13 to < 16 years; 1.5 (male) and 1.4 (female)
• >= 16 years; 1.7 (male) and 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study
regardless of their total and indirect [unconjugated] bilirubin levels as long as
their direct [conjugated] bilirubin is < 3.1 mg/dL)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x
upper limit of normal (ULN) = 135 U/L (within 7 days prior to enrollment). For the
purpose of this study, the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (within 7 days prior to enrollment)
• Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF
result is given as a range of values, then the upper value of the range will be used)
by echocardiogram (within 4 weeks prior to enrollment)
• Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (within 4 weeks
prior to enrollment)
• Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior to
enrollment)
• Platelets >= 100,000/uL (unsupported) (within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (may be supported) (within 7 days prior to enrollment)
• Patients with a known seizure disorder should be stable and should have not
experienced a significant increase in seizure frequency within 2 weeks prior to
enrollment
• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile for
age, height, and gender at the time of enrollment. Patients >= 18 years of age must
have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the
use of antihypertensive medications).
• Note: Adequate blood pressure can be achieved using medication for the treatment
of hypertension
• All patients must have ophthalmology toxicity assessments performed within 4 weeks
prior to enrollment
• For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors)
and/or spine (depending on the site(s) of primary disease) with and without contrast
must be performed within 4 weeks prior to enrollment
• For patients who undergo a surgery on the target tumor (not required), a pre- and
post-operative* MRI of the brain (with orbital cuts for optic pathway tumors) or spine
(depending on the site(s) of primary disease) with and without contrast must also be
performed within 4 weeks prior to enrollment
• The post-operative MRIs should be performed ideally within 48 hours after surgery
if possible
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age
• Patients must have the ability to swallow whole capsules
• Patients must have receptive and expressive language skills in English or Spanish to
complete the quality of life (QOL) and neurocognitive assessments
• All patients and/or their parents or legal guardians must sign a written informed
consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
Exclusion Criteria:
• Patients must not have received any prior tumor-directed therapy including
chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior
surgical intervention is permitted
• Patients with a concurrent malignancy or history of treatment (other than surgery) for
another tumor within the last year are ineligible
• Patients may not be receiving any other investigational agents
• Patients with any serious medical or psychiatric illness/ condition, including
substance use disorders likely in the judgement of the investigator to interfere or
limit compliance with study requirements/treatment are not eligible
• Patients who, in the opinion of the investigator, are not able to comply with the
study procedures are not eligible
• Female patients who are pregnant are not eligible since fetal toxicities and
teratogenic effects have been noted for several of the study drugs. A pregnancy test
is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants are not eligible
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
12 weeks after stopping study therapy are not eligible
• Note: Women of child-bearing potential and males with sexual partners who are
pregnant or who could become pregnant (i.e., women of child-bearing potential)
should use effective methods of contraception for the duration of the study and
for 12 weeks after stopping study therapy to avoid pregnancy and/or potential
adverse effects on the developing embryo
• Cardiac conditions:
• Known genetic disorder that increases risk for coronary artery disease. Note: The
presence of dyslipidemia in a family with a history of myocardial infarction is
not in itself an exclusion unless there is a known genetic disorder documented
• Symptomatic heart failure
• New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy
• Severe valvular heart disease
• History of atrial fibrillation
• Ophthalmologic conditions:
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion or retinal detachment
• Patients with uncontrolled glaucoma
• If checking pressure is clinically indicated, patients with intraocular
pressure (IOP) > 22 mmHg or ULN adjusted by age are not eligible
• Ophthalmological findings secondary to long-standing optic pathway glioma (such
as visual loss, optic nerve pallor, or strabismus) or longstanding
orbito-temporal plexiform neurofibroma (PN), such as visual loss, strabismus)
will NOT be considered a significant abnormality for the purposes of the study
• Treatments and/or medications patient is receiving that would make her/him ineligible,
such as:
• Supplementation with vitamin E greater than 100% of the daily recommended dose.
Any multivitamin containing vitamin E must be stopped prior to study enrollment
even if less than 100% of the daily recommended dosing for vitamin E
• Surgery within 2 weeks prior to enrollment, with the exception of surgical
placement for vascular access or cerebrospinal fluid (CSF) diverting procedures
such as endoscopic third ventriculostomy (ETV) and ventriculo-peritoneal (VP)
shunt.
• Note: Patients must have healed from any prior surgery prior to enrollment
• Patients who have an uncontrolled infection are not eligible
• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH
wild-type by immunohistochemistry [IHC] or sequencing for IDH) established following
either a surgical resection or biopsy. An MRI scan with the required imaging sequences
performed within 21 days prior to randomization preferably. The post-operative MRI
scan performed within 96 hours of surgery or the MRI scan performed for radiation
therapy planning may serve as the MRI scan performed during screening if all required
imaging sequences were obtained.
• Karnofsky performance status ≥ 60% performed within a 14-day window prior to
randomization.
• Availability of tumor tissue representative of GBM from definitive surgery or biopsy.
Recurrent
Inclusion Criteria:
• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH
wild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or second
recurrence after initial standard, control or experimental therapy that includes at a
minimum radiation therapy (RT).
• Evidence of recurrent disease demonstrated by disease progression using slightly
modified Response Assessment in Neuro-Oncology (RANO) criteria.
• Two scans to confirm progression are required: at least 1 scan at the time of
progression and 1 scan prior to the time of progression.
• Karnofsky performance status ≥ 70% performed within a 14-day window prior to
randomization.
• Availability of tumor tissue representative of GBM from initial definitive surgery
and/or, recurrent surgery, if performed.
Newly Diagnosed
Exclusion Criteria:
• Received any prior treatment for glioma including: a. Prior prolifeprospan 20 with
carmustine wafer. b. Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF)
agent. c. Prior radiation treatment for GBM or lower-grade glioma. d. Prior
chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional,
concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of
< 2 years. Patients with prior history of in situ cancer or basal or squamous cell
skin cancer are eligible.
Recurrent
Exclusion Criteria:
• Early disease progression prior to 3 months (12 weeks) from the completion of RT.
• More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line
adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is
considered one line of chemotherapy.)
• Received any prior treatment with lomustine, agents part of any of the experimental
arms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF
receptor-mediated targeted agent.
• Any prior treatment with prolifeprospan 20 with carmustine wafer.
• Any prior treatment with an intracerebral agent.
• Receiving additional, concurrent, active therapy for GBM outside of the trial
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of
< 2 years. Patients with prior history of in situ cancer or basal or squamous cell
skin cancer are eligible.
A Phase II Trial of Poly-ICLC for Low-Grade Gliomas (NF111)
This is a phase II, prospective, longitudinal, multi-center trial of poly-ICLC (Hiltonol ®)
treatment for progressive low-grade gliomas in pediatric patients with NF1. The primary
objective is to evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive
low-grade glioma (LGG) as measured by objective tumor response rate (CR+PR) within the first
48 weeks (12 cycles) of therapy. There will also be secondary and exploratory objectives
listed in the detailed description below.
1. Age: Patients must be less than 22 years at the time of enrollment; there is no lower
age limit.
2. All participants must have an identified pathogenetic constitutional NF1 mutation OR
the clinical diagnosis of NF1 using the NIH Consensus Conference criteria.
3. Diagnosis: LGG (WHO Grade 1 and 2) of the brain and spinal cord are eligible.
Histologic confirmation of tumor is not necessary in the presence of consistent
clinical and radiographic findings. Biopsy for histologic diagnosis is required if
there is clinical suspicion for a high-grade tumor; special attention is recommended
in older adolescents or young adults to the potential for malignant transformation.
Patients with metastatic disease are eligible.
4. Patients must meet at least one of the following criteria for progression or
recurrence of a previously treated target tumor:
1. Progression or recurrence on MRI.
2. New or worsening neurologic symptoms attributable to the target tumor.
3. For patients with OPG: visual worsening, defined as worsening of visual acuity
(VA) or visual fields (VF) documented within the past year by examination or
history, attributable to tumor.
5. Measurable Disease: Patients must have two-dimensional measurable tumor >1cm2.
6. Prior Therapy: Patients must have had at least one prior medical treatment for the
target LGG.
7. Performance Level: Patients must have a performance status of equal or > than 50 using
Karnofsky for patients equal or ≥ 16 years of age and Lansky for patients < 16 years
of age.
8. Patients must have recovered to grade ≤1 from any acute toxicities from all prior
treatments. to enroll on this study and meet time restrictions from end of prior
therapy as defined below:
1. Myelosuppressive chemotherapy: must have received the last dose of
myelosuppressive therapy at least 4 weeks prior to study registration, or at
least 6 weeks if nitrosourea.
2. Investigational/biological agent: Patient must have received the last dose of
other investigational, immunotherapy, or biological agent > 14 days prior to
study registration or at least 5 half-lives, whichever is greater. Bevacizumab
last dose > 36 days prior to enrollment.
3. Radiation therapy: Patients SHOULD NOT have received prior irradiation.
4. Study specific limitations on prior therapy: There is no limit on the number of
prior treatment regimens.
5. Growth factor(s): Must not have received any hematopoietic growth factors within
7 days of study entry or > 14 days if pegylated GCSF is used.
6. Prior surgery: At the time of enrollment, must be ≥ 3 weeks from prior major
surgery such as craniotomy, orthopedic surgery, abdominal surgery or ≥1 week from
minor surgery and completely recovered. Port or central line placement is not
considered a major surgery.
9. Organ Function Requirements:
All patients must have adequate organ function defined as:
9.1 Hematologic Function:
1. Hemoglobin: > 8.0 gm/dl (may transfuse PRBCs)
2. ANC: > 750/mm3. Must be at least 7 days after last dose of growth factor or > 14
days since last dose of pegylated GCSF
3. Platelet Count: > 75,000/mm3 (transfusion independent; ≥ 7 days from last
transfusion)
9.2 Renal Function: Serum creatinine which is less than 1.5 times ULN for age (as per
the table below) or GFR > 70 ml/min/1.73m2
Renal Function Normal for Age
Age Maximum Serum Creatinine (mg/dL) Male Female 1 month to < 6 months 0.4 0.4 6
months to < 1 year 0.5 0.5 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10
years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4
≥ 16 years 1.7 1.4
Liver Function:
1. Total bilirubin < 1.5 x ULN (Children with diagnosis of Gilbert's Syndrome will
be allowed on the study regardless of their total and indirect bilirubin levels
as long as the direct bilirubin is less than 3.1 mg/dL.)
2. SGPT (ALT) ≤ 5 x ULN
3. SGOT (AST) ≤ 5 x ULN
Pulmonary Function:
No evidence of dyspnea at rest, and a pulse oximetry ≥ 92%.
Reproductive Function:
Female patients of childbearing potential must have negative serum or urine pregnancy
test within 7 days prior to the first dose of poly-ICLC. Patient must not be pregnant
or breast-feeding. Patients of childbearing or child-fathering potential must be
willing to use a medically acceptable form of birth control, including abstinence,
while being treated on this study and for 90 days following cessation of treatment.
10. Patient is able to start treatment within 7 days after enrollment.
11. Patients with neurological deficits must be stable for a minimum of 1 week prior to
enrollment.
12. Patients are only eligible if complete resection of the LGG with acceptable morbidity
is not feasible, or if a patient with a surgical option refuses surgery.
13. Parents/legal guardians must provide written informed consent and agree that they will
comply with the study.
Exclusion Criteria:
1. Prior radiation treatment for the low-grade glioma.
2. Prior exposure to poly-ICLC.
3. Patients currently receiving other anti-tumor therapy or experimental therapy
(targeted agents, chemotherapy radiation).
4. Patients with a current or prior diagnosis of malignant glioma (WHO grade III or IV).
5. Patients with a prior diagnosis of malignant peripheral nerve sheath tumor or other
malignancy requiring treatment in the last 48 months.
6. Patients may not have fever (≥38.50 C) within 3 days of enrollment.
7. Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study.
8. Active auto-immune illness.
9. Pregnant or lactating females.
10. Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
90 days after stopping study therapy are not eligible.
11. Severe unresolved infection that requires systemic IV antibiotics.
12. Patients with any significant medical illnesses that in the investigator's opinion
cannot be adequately controlled with appropriate therapy or would compromise the
patient's ability to tolerate this therapy.
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, impaired gastrointestinal function, or psychiatric illness/social
situations that would limit compliance with study requirements.
14. Patients requiring high doses of steroids. Patients may not be on immunosuppressive
therapy, including corticosteroids (with the exception of physiologic replacement,
defined as ≤ 0.75 mg/m2/day dexamethasone or equivalent) at time of enrollment.
However, patients who require intermittent use of bronchodilators or local steroid
injections will not be excluded from the study.
A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (PPMS)
This is a randomized, double blind, controlled, parallel group, multicenter study to evaluate
efficacy, safety and pharmacokinetics of a higher dose of ocrelizumab per intravenous (IV)
infusion every 24 weeks in participants with PPMS, in comparison to the approved 600 mg dose
of ocrelizumab.
• Diagnosis of primary progressive multiple sclerosis (PPMS).
• Expanded disability status scale (EDSS) score at screening and baseline, from 3 to 6.5
inclusive.
• Average T25FWT score over two trials at screening and over two trials at baseline
respectively, up to 150 (inclusive) seconds
• Average 9HPT score over four trials (two trials with each hand) at screening and over
four trials (two trials with each hand) at baseline respectively, up to 250
(inclusive) seconds
• Score of >/= to 2.0 on the Functional Systems scale for the pyramidal system that was
due to lower extremity findings at screening and baseline.
• Documented MRI of brain with abnormalities consistent with MS
• Participants requiring symptomatic treatment for MS and/or physiotherapy must be
treated at a stable dose. No initiation of symptomatic treatment for MS or
physiotherapy within 4 weeks of randomization.
• Participants must be neurologically stable for at least 30 days prior to randomization
and baseline.
• Disease duration from the onset of MS symptoms; if EDSS score at screening is less or
equal to 5, disease duration must be less than 10 years; If EDSS score at screening is
more than 5, disease duration must be less than 15 years
• Documented evidence of the presence of at least one cerebrospinal fluid-specific
oligoclonal bands.
• For females of childbearing potential, agreement to remain abstinent or use adequate
contraceptive methods.
• For female participants without reproductive potential, may be enrolled if
post-menopausal unless receiving a hormonal therapy for her menopause or if surgically
sterile.
Exclusion Criteria:
• History of relapsing remitting or secondary progressive MS at screening.
• Any known or suspected active infection at screening or baseline (except nailbed
infections), or any major episode of infection requiring hospitalization or treatment
with IV antimicrobials within 8 weeks or treatment with oral antimicrobials within 2
weeks, prior to and during screening.
• History of confirmed or suspected progressive multifocal leukoencephalopathy.
• History of cancer, including hematologic malignancy and solid tumors, within 10 years
of screening.
• Immunocompromised state.
• Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization.
• Inability to complete an MRI or contraindication to gadolinium administration.
• Contraindications to mandatory pre-medications for IRRs.
• Known presence of other neurologic disorders that could interfere with the diagnosis
of MS or assessments of efficacy and/or safety during the study.
• Any concomitant disease that may require chronic treatment with systemic
corticosteroids or immunosuppressants during the course of the study.
• Significant, uncontrolled disease that may preclude participant from participating in
the study.
• History of or currently active primary or secondary, non-drug-related,
immunodeficiency.
• Pregnant or breastfeeding or intending to become pregnant.
• Lack of peripheral venous access.
• History of alcohol or other drug abuse within 12 months prior to screening.
• Treatment with any investigational agent or treatment with any experimental procedure
for MS.
• Previous use of anti-CD20s (including ocrelizumab), unless the last infusion was more
than 2 years before screening, B-cell count is normal, and the stop of the treatment
was not motivated by safety reasons or lack of efficacy.
• Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and
daclizumab
• Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline
• Previous treatment with natalizumab within 4.5 months of baseline
• Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2
weeks of baseline
• Previous treatment with any other immunomodulatory or immunosuppressive medication not
already listed above without appropriate washout as described in the applicable local
label. If the washout requirements are not described in the applicable local label,
then the wash out period must be five times the half-life of the medication.
• Any previous treatment with bone marrow transplantation and hematopoietic stem cell
transplantation.
• Any previous history of transplantation or anti-rejection therapy.
• Treatment with intravenous (IV) immunoglobulin (Ig) or plasmapheresis within 12 weeks
prior to randomization.
• Systemic corticosteroid therapy within 4 weeks prior to screening.
• Positive screening tests for active, latent, or inadequately treated hepatitis B
• Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab.
• Any additional exclusionary criterion as per ocrelizumab local label, if more
stringent than the above.
Nivolumab in Treating Patients With Autoimmune Disorders and Advanced, Metastatic, or Unresectable Cancer
This phase Ib trial studies the side effects of nivolumab and to see how well it works in
treating patients with autoimmune disorders and cancer that has spread to other places in the
body or cannot removed by surgery. Immunotherapy with monoclonal antibodies, such as
nivolumab, may help the body's immune system attack the cancer, and may interfere with the
ability of tumor cells to grow and spread.
• Patients can have either histologically confirmed malignancy that is radiologically
evaluable and metastatic or unresectable, or have a malignancy for which a PD-1/PD-L1
inhibitor has been approved in the adjuvant setting. Eligible tumor types include
solid tumors and malignancies in which there is known evidence of clinical activity
for single agent PD-1 or PD-L1 antibodies. Nivolumab is Food and Drug Administration
(FDA)-approved for the treatment of melanoma, non-small cell lung cancer (NSCLC),
Merkel cell cancer, bladder cancer, renal cell carcinoma (RCC), gastric cancer,
hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer, Hodgkin
lymphoma (HL), metastatic small cell lung cancer (SCLC), and any solid tumor with
microsatellite instability (MSI)-high status confirmed. Patients with HL are eligible
but must follow standard response criteria. Additional tumor types may be eligible on
a case by case basis upon discussion with principal investigator (PI). Patients
enrolling on the trial for adjuvant use will be restricted to those with histology for
which a PD-1/PD-L1 inhibitor has been approved in the adjuvant setting including but
not limited to NSCLC, melanoma, RCC, cervical cancer, and bladder cancer
• Patients who have previously received other forms of immunotherapy (high-dose [HD]
IL-2, IFN, CTLA-4) are allowed. Patients must not have received cytokine immunotherapy
for at least 4 weeks before nivolumab administration. Patients who have received prior
anti-CTLA4 will be allowed and the washout period is 6 weeks
• Age >= 18 years; children are excluded from this study but may be eligible for future
pediatric phase 1 combination trials
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Karnofsky >=
60)
• Life expectancy of greater than 12 weeks
• Leukocytes >= 1,000/mcL
• Absolute neutrophil count >= 500/mcL
• Platelets >= 50,000/mcL
• Total bilirubin =< 2 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 x institutional ULN or < 8 x institutional ULN for patients with liver metastases
or an autoimmune disease that is contributing to the elevation of these values
• Creatinine ULN OR glomerular filtration rate (GFR) >= 30 mL/min (if using the
Cockcroft-Gault formula)
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral
therapy with undetectable viral load within 6 months are eligible for this trial
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
undetectable on suppressive therapy if indicated
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV
viral load
• Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate central nervous system (CNS) specific treatment is not required and is
unlikely to be required for at least 4 weeks (or scheduled assessment after the first
cycle of treatment), and a risk-benefit analysis (discussion) by the patient and the
investigator favors participation in the clinical trial
• The effects of nivolumab on the developing human fetus are unknown. For this reason,
women of child-bearing potential (WOCBP) and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. WOCBP receiving nivolumab will be
instructed to adhere to contraception for a period of 5 months after the last dose of
investigational product. Men receiving nivolumab and who are sexually active with
WOCBP will be instructed to adhere to contraception for a period of 7 months after the
last dose of investigational product. Women of childbearing potential must have a
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent
units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of
nivolumab. Women must not be breastfeeding. Women who are not of childbearing
potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic
men) do not require contraception. WOCBP is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12
months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes. In addition, women under the age of 55 must have a documented
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. These durations
have been calculated using the upper limit of the half-life for nivolumab (25 days)
and are based on the protocol requirement that WOCBP use contraception for 5
half-lives plus 30 days, and men who are sexually active with WOCBP use contraception
for 5 half-lives plus 90 days. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she (or the
participating partner) should inform the treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document
• Patients with more than one autoimmune disease are eligible. The treating physician
would determine which autoimmune disease is dominant and the patient would be treated
under that specific cohort
Exclusion Criteria:
• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (AEs) due to agents administered more than 4 weeks
earlier have not resolved or stabilized. Palliative (limited-field) radiation therapy
(RT) is permitted (2 week washout from start of treatment), if all of the following
criteria are met:
• Repeat imaging demonstrates no new sites of bone metastases
• The lesion being considered for palliative radiation is not a target lesion
• Patients with prior therapy with an anti-PD-1 or anti-PD-L1
• Patients with prior allogeneic hematologic transplant
• Patients who are receiving any other anticancer investigational agents
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, gastrointestinal (GI) bleeding, obstruction, and abdominal carcinomatosis
which are known risk factors for bowel perforation should be evaluated for the
potential need for additional treatment before coming on study. For the IBD (UC and
CD) cohort, an endoscopic assessment, disease activity index, and disease specific
inclusion/exclusion criteria will substitute for these factors in determining
eligibility with the exception of abdominal carcinomatosis, which should prompt
further evaluation
Assessment of ANK-700 in Patients With Relapsing Remitting Multiple Sclerosis (MoveS-it)
A safety study of ANK-700 in patients with relapsing remitting multiple sclerosis. The study
has two parts:
Part A - first in human study in which patients receive a single dose of ANK-700 Part B -
patients will receive three doses of either ANK-700 or placebo
• Diagnosed with RRMS per revised McDonald criteria (2017) with an EDSS score ≤ 6.5 at
screening
• Neurologically stable with no evidence of relapse within the 28 days before signing
the informed consent form (ICF)
• Either not currently receiving disease modifying MS therapy, or currently using
fumarate drugs (dimethyl fumarate or diroximel fumarate)
• Patients must use a highly effective method of birth control or are sterile or
postmenopausal as confirmed by study Investigator
• Patient has signed and understands the ICF
Exclusion Criteria:
• Diagnosis of primary progressive MS or secondary progressive MS
• Uncontrolled or significant medical conditions (including active infection or chronic
hepatitis) which, in the opinion of the Investigator, preclude participation
• Patients treated with glatiramer acetate, parenteral steroids or adrenocorticotropic
hormone, β-interferon, plasma exchange, fingolimod, ozanimod, or siponimod within the
3 months prior to first dose
• Patients treated with cytotoxic agents (including, but not limited to, cladribine,
mitoxantrone, cyclophosphamide, azathioprine, and methotrexate), laquinimod,
teriflunomide, or IV gamma globulin within 12 months prior to first dose
• Patients treated with monoclonal antibody therapy (including natalizumab, daclizumab,
rituximab, ofatumumab, and ocrelizumab) within 24 months prior to first dose
• Patients previously treated with alemtuzumab, total lymphoid irradiation, mesenchymal
stem cell or hematopoietic stem cell transplantation, or tolerance-inducing therapies
for MS
• Contraindication to or inability to undergo gadolinium-enhanced magnetic resonance
imaging (MRI) scan
• Use of any investigational drug or experimental procedure within previous 6 months
that would interfere with the assessment of ANK-700
• Patients who are pregnant or breastfeeding
Study to Assess the Efficacy and Safety of MT-3921 in Subjects With Acute Traumatic Cervical Spinal Cord Injury
The purpose of this study is to compare the efficacy and safety of intravenous (IV) infusions
of MT-3921 to placebo in subjects with acute traumatic cervical spinal cord injury.
Subjects meeting eligibility criteria will enter the 6-month double-blind period. Subjects
will be randomized in a 2:1 ratio to receive MT-3921 or placebo in a double blind manner.
Additional screening criteria check may apply for qualification:
• Provide written informed consent prior to beginning any study procedures
• Cervical spinal cord injury that meet all of the following criteria:
• Classified as AIS A, AIS B or AIS C
• ISNCSCI neurological level of injury between C4 and C7 (for C4, the subject must
have at least 1 point of motor activity between C5 to C7)
• UEMS ≤28 at Screening
• Body mass index (BMI) <40
Exclusion Criteria:
Additional screening criteria check may apply for qualification:
• Any concomitant injury that interferes with the procedures and examinations required
by study protocol, including performance, interpretation or validity of neurological
examinations
• Poly-traumatic Injury as defined by Injury Severity Score (ISS) values > 25
• Penetrating spinal cord injuries
• Complete transection of the spinal cord
• Any other significant pre-existing medical conditions prior to spinal cord injury or
current conditions that, in the judgement of the iInvestigator, may increase the risks
associated with study participation
• History of anaphylaxis or clinically significant allergic reactions to any medication
• History or presence of malignancy within the last 3 years prior to screening
• Subjects with current SARS-CoV-2 infection (COVID-19)
• Subjects with hereditary fructose intolerance
• Psychoactive substance use disorder
• Participation in any clinical trial of a new chemical entity within 12 weeks prior to
Screening
• Female subjects who are pregnant or lactating
A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT
This phase II trial studies the best approach to combine chemotherapy and radiation therapy
(RT) based on the patient's response to induction chemotherapy in patients with
non-germinomatous germ cell tumors (NGGCT) that have not spread to other parts of the brain
or body (localized). This study has 2 goals: 1) optimizing radiation for patients who respond
well to induction chemotherapy to diminish spinal cord relapses, 2) utilizing higher dose
chemotherapy followed by conventional RT in patients who did not respond to induction
chemotherapy. Chemotherapy drugs, such as carboplatin, etoposide, ifosfamide, and thiotepa,
work in different ways to stop the growth of tumor cells, either by killing the cells, by
stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high
energy x-rays or high-energy protons to kill tumor cells and shrink tumors. Studies have
shown that patients with newly-diagnosed localized NGGCT, whose disease responds well to
chemotherapy before receiving radiation therapy, are more likely to be free of the disease
for a longer time than are patients for whom the chemotherapy does not efficiently eliminate
or reduce the size of the tumor. The purpose of this study is to see how well the tumors
respond to induction chemotherapy to decide what treatment to give next. Some patients will
be given RT to the spine and a portion of the brain. Others will be given high dose
chemotherapy and a stem cell transplant before RT to the whole brain and spine. Giving
treatment based on the response to induction chemotherapy may lower the side effects of
radiation in some patients and adjust the therapy to a more efficient one for other patients
with localized NGGCT.
• Patients must be >= 3 years and < 30 years at the time of study enrollment
• Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar
and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation
of AFP above institutional normal or > 10 ng/mL or human chorionic gonadotropin (hCG)
beta > 100 mIU/mL. Suprasellar, pineal and bifocal tumors are included. (CSF tumor
markers and cytology must be within 21 days prior to enrollment and within 35 days
prior to start of protocol therapy [repeat if necessary]. Serum tumor markers, AFP and
hCGbeta must be within 7 days prior to enrollment and start of protocol therapy
[repeat if necessary]). Basal ganglia or other primary sites are excluded
• Patients with any of the following pathological elements are eligible: endodermal
sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma
and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant
elements listed above are present. Patients with only mature teratoma are excluded.
Patients with pure germinoma admixed with mature teratoma are excluded (would be
eligible for pure germinoma protocols)
• Patients must have a cranial magnetic resonance imaging (MRI) with and without
gadolinium at diagnosis/prior to enrollment. If surgical resection is performed,
patients must have pre-operative and post operative brain MRI with and without
gadolinium. The post operative brain MRI should be obtained within 72 hours of
surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not
required (within 14 days prior to study enrollment)
• Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to
enrollment. Spine MRI with and without gadolinium is recommended (within 14 days prior
to study enrollment)
• Lumbar CSF must be obtained prior to study enrollment unless medically
contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be
obtained at the time of surgery, then it should be performed at least 10 days
following surgery and prior to study enrollment. False positive cytology can occur
within 10 days of surgery
• Patients must have CSF tumor markers obtained prior to enrollment unless medically
contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if
performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF
diversion and biopsy/surgery are combined, CSF tumor markers should be collected first
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
enrollment)
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
enrollment)
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days
prior to enrollment)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days
prior to enrollment):
• Age: Maximum serum creatinine (mg/dL)
• 3 to < 6 years: 0.8 (male), 0.8 (female)
• 6 to < 10 years: 1 (male), 1 (female)
• 10 to < 13 years: 1.2 (male), 1.2 (female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: male (1.7), 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L (within 7 days prior to enrollment)
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
value of 45 U/L
• Central nervous system function defined as:
• Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled
• Patients must not be in status epilepticus, coma or assisted ventilation prior to
study enrollment
• Protocol therapy must begin within 31 calendar days of definitive surgery or clinical
diagnosis. If a biopsy only was performed, the biopsy date will be considered the date
of definitive surgery. For patients who have a biopsy or incomplete resection at
diagnosis followed by additional surgery, the date of the last resection will be
considered the date of definitive surgery.
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
• NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:
• English-, Spanish-, or French- speaking
• Note: Patients who speak a language other than English, Spanish, or French will
be allowed to participate in ACNS2021 but will not complete the neurocognitive
and quality of life assessments
• No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g.,
Down syndrome, fragile X, William syndrome, intellectual disability). Patients with
NF1 will be allowed to participate
• Additional eligibility criteria for the COG Standardized Neuropsychological Battery
only: must be at a site that has a psychologist to administer the battery
• Note: If not eligible for the COG Standardized Battery, patients should still
complete the Behavior Rating Inventory of Executive Function, Second Edition
(BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior
Assessment System Third Edition (ABAS-3), and Behavior Assessment System for
Children, Third Edition (BASC-3) questionnaires
Exclusion Criteria:
• Patients with tumors located outside the ventricles (i.e., basal ganglia, thalamus)
• Patients with only mature teratoma and non-elevated markers upon tumor sampling at
diagnosis
• Patients who have received any prior tumor-directed therapy for their diagnosis of
NGGCT other than surgical intervention and corticosteroids
• Patients with metastatic disease (i.e., MRI evaluation, lumbar CSF cytology or
intraoperative evidence of dissemination)
• Female patients who are pregnant, since fetal toxicities and teratogenic effects have
been noted for several of the study drugs
• Note: Serum and urine pregnancy tests may be falsely positive due to
HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by
institutional standards
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation
Olanzapine Versus Megestrol Acetate for the Treatment of Loss of Appetite Among Advanced Cancer Patients
This phase III trial compares the effects of olanzapine versus megestrol acetate in treating
loss of appetite in patients with cancer that has spread to other places in the body
(advanced). Olanzapine may stimulate and increase appetite. This study aims to find out if
olanzapine is better than the usual approach (megestrol acetate) for stimulating appetite and
preventing weight loss.
• Women and men of reproductive potential should agree to use an appropriate method of
birth control throughout their participation in this study due to the teratogenic
potential of the therapy utilized in this trial. Appropriate methods of birth control
include abstinence, oral contraceptives, implantable hormonal contraceptives or double
barrier method (diaphragm plus condom)
• Diagnosis of advanced cancer
• Patient-reported 2-month weight loss of at least 5 pounds (2.3 kilograms) and/or
physician-estimated caloric intake of less than 20 calories/kilogram of body weight
per day
• The patient must perceive loss of appetite and/or weight as a problem; and have an
appetite score of 4 or worse on the "Please rate your appetite…." question that
requires a patient response on a 0-10 numeric rating scale
• Not receiving ongoing tube feedings or parenteral nutrition at the time of
registration
• Not currently using systemic adrenal steroids (with the exception of short-term
dexamethasone within 3 days of chemotherapy for control of chemotherapy side effects)
• No use of androgens, progesterone analogs, or other appetite stimulants within the
past month
• Patient should not have poorly controlled hypertension or congestive heart failure at
registration
• Patient should not have an obstruction of the alimentary canal, malabsorption, or
intractable vomiting (defined as vomiting more than 3 times per day over the preceding
week)
• Not currently using olanzapine for another medical condition or had previously used
olanzapine for chronic nausea or for any pre-existing psychotic disorder
• Patient should not have had a previous blood clot at any time in the past
• No history of poorly controlled diabetes
• No symptomatic leptomeningeal disease or known brain metastases as these patients may
have difficulty taking oral medications
• No history of hypersensitivity to olanzapine or megestrol acetate
• No COVID-19 infection in the past that, in the opinion of the treating physician, had
left patients with compromised taste, which has not resolved at the time of
registration
• Not pregnant and not nursing, because this study involves an investigational agent
whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
are unknown. Therefore, for women of childbearing potential only, a negative urine or
serum pregnancy test done =< 14 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Estimated life expectancy of 3 months or longer
• Serum creatinine =< 2.0 mg/dL
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x upper limit
of normal (ULN)
• Fasting glucose > 1410 mg/dl
• Granulocytes > 1000/hpf
• No treatment with another antipsychotic agent, such as risperidone, quetiapine,
clozapine, butyrophenone within 30 days of enrollment
• In order to complete the mandatory patient-completed measures, participants must be
able to speak and/or read English or Spanish. Sites seeking to enroll Spanish-speaking
patients should have access to Spanish speaking staff on site or through the use of a
translation service to be able to conduct the informed consent discussion in Spanish,
and to conduct the weekly phone calls
Exclusion Criteria:
• Psychiatric illness which would prevent the patient from giving informed consent
• Medical condition such as uncontrolled infection (including human immunodeficiency
virus [HIV]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion
of the treating physician, would make this protocol unreasonably hazardous for the
patient
• Patients who cannot swallow oral formulations of the agents
• Patients with impaired decision-making capacity (such as with a diagnosis of dementia
or memory loss) are not eligible for this study
• No presence of a hormone-sensitive tumor, such as breast, endometrial, or prostate
cancer (this exclusion criterion is intended to circumvent any confounding
antineoplastic effects of megestrol acetate)
• life expectancy of less than 24 hours
• anoxic brain injury or an uncontrolled metabolic condition as primary cause of SE
• treatment of current SE episode with IV anesthetics
Drug: Ganaxolone, Drug: Placebo
Epilepsy, Status Epilepticus, Convulsive Status EPILEPTICUS, Non-Convulsive Status Epilepticus
Effect on Body Movement and Mental Skills in Patients Who Received Gadolinium-based Contrast Media for Magnetic Resonance Examination Multiple Times Within 5 Years (ODYSSEY)
This study is a postmarketing requirement jointly carried out by four NDA holders (Bayer AG,
Bracco, GE Healthcare and Guerbet) and the CRO IQVIA.
The study aims to create detailed images of the organs and tissue of the human body during
x-ray, CT-scan or MRI investigations, doctors are using contrast media (a kind of dye) which
can be given to patients by injection into a blood vessel or by mouth.
In this study researchers want to find out whether so called gadolinium-based contrast agents
(GBCAs) have an effect on body movement and mental skills when given to participants multiple
times within 5 years.
The study plans to enroll about 2076 participants suffering from a condition for which they
are likely to have at least annually a MRI or another imaging examinations. Only adults up to
65 years will be considered to join this study. During the study duration of 5 years
participants will receive annually a MRI or other imaging tests (such as CT-scan, x-ray) and
will visit the study doctor at least 7 times for physical examinations, laboratory
investigations and tests on body movement and mental skills.
• Participant must be neurologically normal, defined as free of unstable neurologic and
psychiatric disease as confirmed by a normal neurologic examination at screening
• Participant (GBCA-exposed or controls) agrees to undergo unenhanced magnetic resonance
imaging (UE-MRI) of the brain at enrollment and at the end of the observation period
(5 years)
• Participants should have at least 1 of the following indications: a) Medium to high
risk for breast cancer or dense breasts undergoing breast cancer screening with MRI,
b) Elevated prostate-specific antigen (PSA) and under active diagnostic surveillance
for prostate cancer, c) Chronic liver disease (eg, liver cirrhosis limited to Child
class A, post-hepatitis chronic hepatopathy, or primary sclerosing cholangitis) for
surveillance of hepatocellular carcinoma development, d) Low-grade colorectal cancer
or neuroendocrine tumor undergoing screening for liver metastases or e) Branch-duct
intraductal papillary mucinous neoplasm (IPMN) of the pancreas (maximum size ≤2 cm)
undergoing imaging surveillance.
In addition, for participants in the GBCA Arms only:
• Each participant should be likely to undergo ≥5 GBCA-enhanced MR examinations with the
same GBCA at least annually throughout the 5-year study duration
• Prospective participants with up to 3 well documented GBCA administrations prior to
study screening are acceptable, provided that the imaging was performed with the same
GBCA as the one to be prospectively used in the study. If the GBCA used cannot be
identified, he/she cannot be enrolled.
For the Control Arm:
• Participants who never had and are not likely to receive any GBCA injection during the
course of the study
• Each control participant must be willing to undergo UE-MRI of the brain at baseline
and at Year 5. In Years 1 to 4, the control participants will undergo their clinically
indicated UE-MRIs, computed tomography (CT), ultrasound, or X-ray procedures
Exclusion Criteria:
• As evidenced by history or determined in the neurologic exam at screening, concurrent
neurological and/or psychiatric disease (or treatments) that could influence the
results of the study's motor and cognitive tests (e.g. Cerebrovascular disease,
Multiple sclerosis, Neurodegenerative disease, Malignant disease other than listed in
indications, Carcinoid tumors, Epilepsy, Prior neurosurgery, Psychotic disorders or
any prior psychotic episode not otherwise specified •any documented prior history of
chronic schizophrenia, Remittent or current medically confirmed major depressive
disorder or bipolar disorder, History of long-term major depression or bipolar
affective disorder with an active episode in the past 2 to 5 years, Neurodevelopmental
disorders (eg, trisomy 21), Uncontrolled severe migraine, Uncontrolled or controlled
anxiety or depression within 6 months before enrollment, Screening scores of ≤24 on
the MMSE and/or ≥11 on the Hospital Anxiety and Depression Scale (HADS)).
• Prior, planned, or ongoing chemotherapy or brain irradiation
• Use of concomitant medication(s) affecting neuro-cognitive or motor function
• Substance or alcohol abuse as determined by the investigator
• Alcoholic cirrhosis
• Renal disease, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73
m2
• History of environmental/occupational/other exposure to one or more chemicals that may
affect cognitive and/or motor function, including, but not limited to, heavy metals
(arsenic [As], cadmium [Cd], lead [Pb], manganese [Mn], and mercury [Hg]), pesticides,
solvents, or carbon monoxide.
• Clinical indications requiring >1 contrast enhanced magnetic resonance imaging
(CE-MRI) every 6 months
• Pregnant or nursing (lactating) women
• Presence of any metal-containing joint implants/prostheses
In addition, for participants in either of the GBCA Arms only:
•Receipt of a GBCA or generic prior to study entry other than the specific GBCA to be
administered during the course of the study.
For participants in the Control Arm only:
• Participants with any previous exposure to a GBCA.
• Participants with any contraindication to UE-MRI examinations.
Procedure: Motor Tests, Procedure: Cognitive Tests, Procedure: Unenhanced-MRI of the brain, Procedure: Gadolinium Measurements, Drug: Gadoxetate disodium, Drug: Gadobenate dimeglumine, Drug: Gadodiamide, Drug: Gadoterate meglumine, Drug: Gadobutrol, Drug: Gadoteridol
Breast - Female, Breast - Male, Colon, Liver, Other Endocrine System, Pancreas, Prostate, Rectum, Motor Function, Cognitive Function, Contrast Media
Motor function assessment, Cognitive function assessment, Magnetic Resonance Imaging (MRI), Gadolinium, Gadolinium-based contrast agent (GBCA), Gadolinium retention, Breast cancer, Prostate cancer, Hepatocellular carcinoma, Colorectal cancer, Neuroendocrine tumor, Branch-duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas
The Synuclein-One Study will be evaluating α-synuclein in patients with Parkinson's disease,
Multiple System Atrophy, Dementia with Lewy bodies and Pure Autonomic Failure. Using a simple
diagnostic test will improve clinical accuracy in diagnosing, earlier diagnosis, and
distinguish between neurodegenerative diseases.
• Male and female between 40-99 years of age
• Prior clinical diagnosis of Parkinson's disease, Multiple System Atrophy, Dementia
with Lewy bodies or Pure Autonomic Failure
• Health Subjects, no history of clinical or symptoms suggestive with synucleinopathy
Exclusion Criteria:
• Clinical evidence of severe vascular disease (history of ulceration, poor wound
healing, vascular claudication)
• Clinically active coronary artery or cerebrovascular disease
• Current smoker or alcoholism
• History of allergic reaction to local anesthesia for skin biopsies
• Use of blood thinners (aspirin or Plavix alone is allowed)
• Significantly impaired wound healing or history of scarring or keloid formation
• Healthy individuals or individuals with synucleinopathy is disease may be explained by
other causes: recent history of encephalitis, Cortical dementia of Alzheimer's type,
Whipple's disease, toxin exposure, repeated head injury and stepwise disease
progression suggestive of vascular etiology
Diagnostic Test: Skin Biopsy
Multiple System Atrophy, Parkinson Disease, Pure Autonomic Failure, Brain and Nervous System, Dementia With Lewy Bodies
A Gene Transfer Therapy Study to Evaluate the Safety and Efficacy of SRP-9001 in Participants With Duchenne Muscular Dystrophy (DMD) (EMBARK)
The study will evaluate the safety and efficacy of gene transfer therapy in boys with DMD. It
is a randomized, double-blind, placebo-controlled study. The participants who are randomized
to the placebo arm will have an opportunity for treatment with gene transfer therapy at the
beginning of the second year.
• Is ambulatory and from 4 to under 8 years of age at time of randomization.
• Definitive diagnosis of DMD based on documented clinical findings and prior genetic
testing.
• Ability to cooperate with motor assessment testing.
• Stable daily dose of oral corticosteroids for at least 12 weeks prior to Screening,
and the dose is expected to remain constant throughout the study (except for
modifications to accommodate changes in weight).
• rAAVrh74 antibody titers are not elevated as per protocol-specified requirements.
Exclusion Criteria:
• Exposure to gene therapy, investigational medication, or any treatment designed to
increase dystrophin expression within protocol specified time limits.
• Abnormality in protocol-specified diagnostic evaluations or laboratory tests.
• Presence of any other clinically significant illness, medical condition, or
requirement for chronic drug treatment that in the opinion of the Investigator creates
unnecessary risk for gene transfer.
Other inclusion or exclusion criteria could apply.
Genetic: SRP-9001, Genetic: Placebo
Duchenne Muscular Dystrophy, Other
Muscular Dystrophies, Duchenne Muscular Dystrophy, DMD, North Star Ambulatory Assessment (NSAA), Ambulatory, Pediatric, Gene-Delivery
A Study to Test if Fremanezumab is Effective in Preventing Chronic Migraine in Patients 6 to 17 Years of Age
The primary objective of the study is to evaluate the effectiveness of fremanezumab as
compared to placebo for the preventive treatment of chronic migraine (CM).
Secondary objectives are to further demonstrate the efficacy of Fremanezumab as compared to
placebo for the preventive treatment of CM, to evaluate the safety and tolerability of
Fremanezumab in the preventive treatment of CM and to evaluate the immunogenicity of
Fremanezumab and the impact of antidrug antibodies (ADAs) on clinical outcomes in
participants exposed to Fremanezumab
The total duration of the study is planned to be 48 months.
• The participant has a clinical history of recurrent headache consistent with the
diagnosis of migraine for at least 6 months before screening, consistent with ICHD-3
criteria (Headache Classification Committee of the IHS 2013), and a history of ≥15
headache days per month, of which ≥8 headache days were assessed as migraine days per
month in each of the 3 months prior to screening (visit 1).
• The participant or parent/caregiver maintain a prospectively collected headache diary
• The participant does not have chronic daily headache. For the purposes of this study,
chronic daily headache is operationally defined as <4 headache-free days during the
28-day baseline period.
NOTE: Additional criteria apply; please contact the investigator for more information.
Exclusion Criteria:
• The participant is using medications containing opioids (including codeine) or
barbiturates (including Fiorinal®, Fioricet®, or any other combination containing
butalbital) for the treatment of migraine during the 3 months prior to the day of the
screening visit.
• The participant has used an intervention/device (eg, scheduled nerve block or
transcranial magnetic stimulation) for the treatment of migraine or in the head or
neck area for any condition during the 2 months prior to the day of the screening
visit.
• The participant has a current history of a clinically significant psychiatric
condition, any prior history of a suicide attempt, or a history of suicidal ideation
with a specific plan within the past 2 years, at the discretion of the investigator.
• The participant has an ongoing infection or a known history of human immunodeficiency
virus infection, tuberculosis, Lyme disease, or chronic hepatitis B or C, or a known
active infection of coronavirus disease 2019 (COVID-19).
• The participant has a past or current history of cancer.
• The participant is pregnant, nursing.
• The participant has a history of hypersensitivity reactions to injected proteins,
including mAbs, or a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis
syndrome, or the participant is concomitantly using lamotrigine.
• The participant received a live attenuated vaccine (eg, intranasal flu vaccine, and
measles, mumps, and rubella vaccine) within the 12-week period prior to screening.
Note: If a medical need arises during the study, the participant may receive a live
attenuated vaccine.
• The patient has a current or past medical history of hemiplegic migraine.
NOTE: Additional criteria apply; please contact the investigator for more information.
A Study of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling
This is a Phase 1/2, multicenter, open-label trial of avapritinib in patients aged 2 to less
than 18 years of age with with relapsed/refractory (R/R) solid tumors with mutations
(including non-synonymous point mutations, insertions, and deletions) in KIT or PDGFRA, or
gliomas with the H3K27M mutation, and no available alternative treatment options. This is a
single-arm trial in which all patients will receive avapritinib. The study consists of 2
parts: dose confirmation, safety, and PK (Part 1) and initial efficacy, safety, and PK at the
Part 2 recommended dose (Part 2).
• Patient has confirmed diagnosis of a R/R solid or CNS tumor with a mutation in KIT or
PDGFRA (confirmed by local mutational testing of tumor sample) that has progressed
despite standard therapy and no alternative treatment option is available OR Confirmed
diagnosis of H3K27M mutant glioma that has failed standard therapy or for which no
standard therapy that may convey clinical benefit exists, as judged by the
Investigator.
• Patients with CNS disease should be on a stable dose (≤10% change) of corticosteroids
for at least 7 days prior to first dose of avapritinib, with no plans for dose
escalation.
• Disease extent
1. Part 1: All patients must have at least 1 measurable lesion as defined by RECIST
v1.1 or RANO (for CNS tumors). If radiation therapy has been administered, at
least
1 measurable lesion must not have been irradiated, or must have clearly
progressed since being irradiated.
2. Part 2: At least one measurable lesion as defined by RECIST v1.1 (RANO for CNS
tumors). If radiation therapy has been administered, at least 1 measurable lesion
must not have been irradiated within the previous 12 weeks, or must have clearly
progressed since being radiated (per RANO). For up to 5 patients with H3K27M
mutant gliomas where there is no standard therapy that may convey clinical
benefit as judged by the investigator, progression of disease of a measurable
lesion after irradiation is not required.
• A Lansky (≤16 years of age) or Karnofsky (>16 years of age) score of at least 50. If
the patient is unable to walk due to paralysis, but is mobile in a wheelchair, the
patient is considered ambulatory for the purpose of assessing their performance
status.
• Patient agrees to utilize contraception consistent with local regulations
Exclusion Criteria:
• Patient has any of the following within 14 days before the first dose of study
treatment:
1. Platelet count <75 × 109/L (<100 × 109/L if a CNS tumor).
2. Absolute neutrophil count (ANC) <1.0 × 109/L.
3. Hemoglobin <8.0 g/dL (RBC transfusion ≥14 days before test is permitted to meet
criterion).
4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × the upper
limit of normal (ULN) for age; except in patients with tumor involvement of the
liver who must not have AST and ALT >5 × ULN for age.
5. Total bilirubin >1.5 mg/dL for age; and in presence of Gilbert's syndrome, total
bilirubin.
> 3 × ULN or direct bilirubin > 1.5 × ULN.
6. Serum creatinine >1.5 × ULN for age.
7. International normalized ratio (INR) or prothrombin time (PT) >ULN (>1.5 × ULN if
on prophylactic reversible anticoagulants).
• Patient has a QT interval corrected using Fridericia's formula (QTcF) >470 msec.
Patient has a familial or personal history of prolonged QT syndrome or Torsades de
pointes.
• Patient has clinically significant, uncontrolled, cardiovascular disease including
congestive heart failure Grade III or IV according to the New York Heart Association
(NYHA) classification; myocardial infarction or unstable angina within the previous 6
months, uncontrolled hypertension (>99th percentile for age), or clinically
significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT
prolongation (eg, Type II second degree heart block or third-degree heart block).
• Patient received the following systemic antineoplastic therapies:
1. Systemic antineoplastic therapy (including experimental therapy within 5
half-lives or 28 days [6 weeks if prior nitrosurea], whichever is shorter).
2. Focal external beam radiotherapy, including stereotactic radiosurgery, within 6
weeks prior to the first dose of avapritinib to either target or non-target
lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery,
within 2 weeks of the first dose of avapritinib (within 6 weeks for patients with
CNS tumors). Craniospinal irradiation within 12 weeks prior to the first dose of
avapritinib.
3. All AEs related to other antineoplastic therapies (eg, systemic antineoplastics,
radiotherapy) must have resolved to Grade ≤1 (Grade ≤2 for peripheral neuopathy
and/or ototoxicity) prior to the first dose of avapritinib.
• Patient has previously received treatment with avapritinib.
• Patient received autologous stem cell transplant (SCT) following myeloablative therapy
or chimeric antigen receptor T cell (CAR-T) therapy within 3 months prior to the first
dose of avapritinib or prior allogeneic SCT within 1 year and no evidence of Grade 1
or greater graft-versus-host disease and no immunosuppressants for graft-versus-host
disease (steroids for primary malignancy being permitted). Patients who received stem
cell reinfusion following nonmyeloablative therapy are eligible once they meet the
peripheral blood count criteria in Exclusion Criterion #1.
• Patient requires on going treatment or has received treatment within 28 days before
the start of avapritinib administration with drugs or foods that are strong CYP3A
inhibitors or inducers or EIAEDs (eg, carbamazepine, phenytoin, phenobarbital, and
primidone). Please refer to Appendix 1 for a list of these drugs and/or foods.
• Patient has had a major surgical procedure within 14 days of the first dose of study
treatment (procedures such as central venous catheter placement, tumor needle biopsy,
and feeding tube placement are not considered major surgical procedures).
• Patient has a history of another primary malignancy that has been diagnosed or
required therapy within 3 years before the first dose of avapritinib. The following
prior malignancies are not exclusionary: completely resected basal cell and squamous
cell skin cancer, curatively treated localized prostate cancer, and completely
resected carcinoma in situ of any site.
• Female subjects of childbearing potential who are unwilling, if not post-menopausal or
surgically sterile, to abstain from sexual intercourse or employ highly effective
contraception from the time of informed consent and for at least 6 weeks after the
last dose of study treatment. Male subjects who are unwilling, if not surgically
sterile, to abstain from sexual intercourse or employ highly effective contraception
from the time of informed consent and for at least 6 weeks after the last dose of
study treatment. Refer to Section 5.4.2 for acceptable methods of contraception.
• Patient is pregnant
• Patient is breastfeeding.
• Patient has prior or ongoing clinically significant illness, medical condition,
surgical history, physical finding, or laboratory abnormality that, in the
Investigator's opinion, could affect the safety of the patient; alter the absorption,
distribution, metabolism, or excretion of the study drug; or impair the assessment of
study results.
• History of thrombosis requiring treatment within the past 6 months.
• Patients who require anticoagulants, with the exception of stable doses of
prophylactic reversible anticoagulants.
• Patients who are unable to swallow tablets (in Part 1) or mini-tablets (in Part 2)
within the sprinkle capsules.
• Patients with a known risk of intracranial bleeding, such as a brain aneurysm that has
not been removed or repaired, or a history of intracranial bleeding within the past
year, or radiographic evidence of hemorrhage on Screening MRI. Exceptions are patients
with primary CNS tumors who are eligible unless CNS bleeding has occurred within 2
weeks of the first dose of avapritinib and patients with punctate hemorrhages <3 mm.
• History of a seizure disorder that is not well controlled on current antiepileptic
medications. EIAEDs carbamazepine, phenytoin, phenobarbital, and primidone are
prohibited.
• Patient is unwilling or unable to comply with scheduled visits, treatment
administration plan, laboratory tests, or other study procedures and study
restrictions
A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine (DIPG) Glioma and High-Grade Glioma (HGG)
This phase I/II trial tests the safety, side effects, and best dose of selinexor given in
combination with standard radiation therapy in treating children and young adults with newly
diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) with a genetic
change called H3 K27M mutation. It also tests whether combination of selinexor and standard
radiation therapy works to shrink tumors in this patient population. Glioma is a type of
cancer that occurs in the brain or spine. Glioma is considered high risk (or high-grade) when
it is growing and spreading quickly. The term, risk, refers to the chance of the cancer
coming back after treatment. DIPG is a subtype of HGG that grows in the pons (a part of the
brainstem that controls functions like breathing, swallowing, speaking, and eye movements).
This trial has two parts. The only difference in treatment between the two parts is that some
subjects treated in Part 1 may receive a different dose of selinexor than the subjects
treated in Part 2. In Part 1 (also called the Dose-Finding Phase), investigators want to
determine the dose of selinexor that can be given without causing side effects that are too
severe. This dose is called the maximum tolerated dose (MTD). In Part 2 (also called the
Efficacy Phase), investigators want to find out how effective the MTD of selinexor is against
HGG or DIPG. Selinexor blocks a protein called CRM1, which may help keep cancer cells from
growing and may kill them. It is a type of small molecule inhibitor called selective
inhibitors of nuclear export (SINE). Radiation therapy uses high energy to kill tumor cells
and shrink tumors. The combination of selinexor and radiation therapy may be effective in
treating patients with newly-diagnosed DIPG and H3 K27M-Mutant HGG.
• STEP 0: Patients must be >= 12 months and =< 21 years of age at the time of enrollment
on Step 0.
• Please note:
• This age range includes pre-screening for all HGG patients. Individual
treatment protocols may have different age criteria.
• Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are
>= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).
• STEP 0: Patient is suspected of having localized, newly diagnosed HGG, excluding
metastatic disease, OR patient has an institutional diagnosis of DIPG
• STEP 0:
• For patients with non-pontine tumors: Patient and/or their parents or legal
guardians have signed informed consent for eligibility screening on APEC14B1 Part
A.
• For patients with DIPG: Patient and/or their parents or legal guardians have
signed informed consent for ACNS1821.
• STEP 0:
• For patients with non-pontine tumors only, the specimens obtained at the time of
diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably
within 5 calendar days of definitive surgery
• STEP 1: Patients must be >= 12 months and =< 21 years of age at the time of enrollment
• STEP 1: Patients must have newly-diagnosed DIPG or HGG (including DMG).
• STEP 1: Stratum DIPG
• Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine
epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial
T2 weighted image, are eligible. No histologic confirmation is required.
• Patients with pontine tumors that do not meet radiographic criteria for typical
DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine
cross-sectional area with or without extrapontine extension) are eligible if the
tumors are biopsied and proven to be high-grade gliomas (such as anaplastic
astrocytoma, glioblastoma, high-grade glioma not otherwise specified [NOS],
and/or H3 K27M-mutant) by institutional diagnosis.
• STEP 1: Stratum DMG (with H3 K27M mutation)
• Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF
V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1
• Note: Patients need not have either measurable or evaluable disease, i.e., DMG
patients may have complete resection of their tumor prior to enrollment. Primary
spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in
non-midline structures (e.g., cerebral hemispheres), these patients will be
considered part of Stratum DMG.
• STEP 1: Stratum HGG (without H3 K27M mutation)
• Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF
V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1
• Please note:
• Patients who fall in this category and who are >= 18 years of age are not
eligible due to another standard-of-care regimen (radiation/temozolomide)
that is available
• Patients need not have either measurable or evaluable disease, i.e., HGG
patients may have complete resection of their tumor prior to enrollment.
Primary spinal tumors are eligible for enrollment
• STEP 1: Patients must have a performance status corresponding to Eastern Cooperative
Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of
age and Lansky for patients =<16 years of age. Patients who are unable to walk because
of paralysis, but who are up in a wheelchair, will be considered ambulatory for the
purpose of assessing the performance score.
• STEP 1: Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
step 1 enrollment)
• STEP 1: Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
step 1 enrollment)
• STEP 1: Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within
7 days prior to step 1 enrollment)
• STEP 1: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 (within 7 days prior to step 1 enrollment) or
A serum creatinine based on age/gender as follows (within 7 days prior to step 1
enrollment):
• Age / Maximum Serum Creatinine (mg/dL)
• 1 to < 2 years / male: 0.6; female: 0.6
• 2 to < 6 years / male: 0.8; female: 0.8
• 6 to < 10 years / male: 1; female: 1
• 10 to < 13 years / male: 1.2; female: 1.2
• 13 to < 16 years / male: 1.5; female: 1.4
• >= 16 years / male: 1.7; female: 1.4
• STEP 1: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• STEP 1: Serum glutamate pyruvate transaminase (SGPT) (alanine
aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN
for SGPT is 45 U/L.
• STEP 1: Serum amylase =< 1.5 x ULN
• STEP 1: Serum lipase =< 1.5 x ULN
• STEP 1: No evidence of dyspnea at rest, no exercise intolerance, and a pulse
oximetry > 94% if there is clinical indication for determination.
• STEP 1: Patients with seizure disorder may be enrolled if on anticonvulsants
and well controlled.
• STEP 1: Patients must be enrolled and protocol therapy must begin no later
than 31 days after the date of radiographic diagnosis (in the case of
non-biopsied DIPG patients only) or definitive surgery, whichever is the
later date (Day 0).
For patients who have a biopsy followed by resection, the date of resection will be
considered the date of definitive diagnostic surgery. If a biopsy only was performed, the
biopsy date will be considered the date of definitive diagnostic surgery.
Exclusion Criteria:
• STEP 1: Patients must not have received any prior therapy for their central nervous
system (CNS) malignancy except for surgery and steroid medications.
• STEP 1: Patients who are currently receiving another investigational drug are not
eligible.
• STEP 1: Patients who are currently receiving other anti-cancer agents are not
eligible.
• STEP 1: Patients >=18 years of age who have H3 K27M-wild type HGG.
• STEP 1: Patients who have an uncontrolled infection.
• STEP 1: Patients who have received a prior solid organ transplantation.
• STEP 1: Patients with grade > 1 extrapyramidal movement disorder.
• STEP 1: Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.
• STEP 1: Patients with metastatic disease are not eligible; MRI of spine with and
without contrast must be performed if metastatic disease is suspected by the treating
physician.
• STEP 1: Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the
exception of H3 K27M-mutant bithalamic tumors.
• STEP 1: Patients who are not able to receive protocol specified radiation therapy.
• STEP 1:
• Female patients who are pregnant are ineligible since there is yet no available
information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed
their infants. It is not known whether selinexor is excreted in human milk.
• Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they
have agreed to use two effective methods of birth control (including a medically
accepted barrier method of contraception, e.g., male or female condom) for the
duration of their study participation and for 90 days after the last dose of
selinexor. Abstinence is an acceptable method of birth control.
• Subject has a clinical diagnosis of epilepsy and, in the opinion of the Investigator,
may need benzodiazepine intervention for seizure control.
• Subjects having either partial or generalized epilepsy with motor seizures or seizures
with clear alteration of awareness, for which rescue medications have been used at
least once in the last 3 months or in the opinion of the investigator, may need a
benzodiazepine intervention for seizure control 1-2 times every 3 months on average.
Exclusion Criteria:
• Subjects whose body weight are < 6 kg or > 33 kg.
• Subject is undergoing intracranial electroencephalogram (EEG) monitoring.
• In the opinion of the investigator, a history of clinically significant medical
history that would jeopardize the safety of the subject or impact the validity of the
study results (such as significant gastrointestinal, renal, nasal polyps or any nasal
passage abnormality that could interfere with nasal spray administration.
• Subject has had significant traumatic injury, major surgery or open biopsy within 30
days prior to study screening.
• Participation in a clinical trial within 30 days prior to the first dose of study
drug.
• Inadequate or difficult venous access that may jeopardize the quality or timing of the
PK samples.
Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
This Pediatric MATCH screening and multi-sub-study phase II trial studies how well treatment
that is directed by genetic testing works in pediatric patients with solid tumors,
non-Hodgkin lymphomas, or histiocytic disorders that have progressed following at least one
line of standard systemic therapy and/or for which no standard treatment exists that has been
shown to prolong survival. Genetic tests look at the unique genetic material (genes) of
patients' tumor cells. Patients with genetic changes or abnormalities (mutations) may benefit
more from treatment which targets their tumor's particular genetic mutation, and may help
doctors plan better treatment for patients with solid tumors or non-Hodgkin lymphomas.
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must be >= 12 months and
=< 21 years of age at the time of study enrollment
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients with recurrent or
refractory solid tumors, including non-Hodgkin lymphomas, histiocytoses (e.g.
langerhans cell histiocytosis [LCH], juvenile xanthogranuloma [JXG], histiocytic
sarcoma), and central nervous system (CNS) tumors are eligible; patients must have had
histologic verification of malignancy at original diagnosis or relapse except in
patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with
pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers
including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG); in cases where
patient enrolls prior to histologic confirmation of recurrent disease, patient is
ineligible and should be withdrawn from study if histology fails to confirm
recurrence; please note: Patients with Hodgkin lymphoma and plexiform neurofibroma are
not eligible
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor Testing Requirement: Tumor
sample availability requirement for stage 1 of Pediatric MATCH (patients enrolled from
start of study in July 2017 through 12/31/21); Patients must have an formalin-fixed
paraffin-embedded (FFPE) tumor sample available for MATCH study testing from a biopsy
or surgery that was performed at any point after initial tumor recurrence/progression,
or be planned to have a procedure to obtain such a sample that is considered to be of
potential benefit by the treating clinicians; a tumor sample from a clinically
performed diagnostic (pre-treatment) biopsy will be acceptable for enrollment onto
Pediatric MATCH only for children with high-grade gliomas of the brainstem (diffuse
intrinsic pontine gliomas) or thalamus
• Please note: Samples that have been decalcified using standardly utilized
acid-based decalcification methods are not generally suitable for MATCH study
testing; the nucleic acids will have been degraded in the decalcification process
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor molecular profiling report
availability requirement for Stage 2 of Pediatric MATCH (patients enrolled starting
2022): In stage 2 of the study, no tumor samples will be submitted for centralized
clinical tumor profiling; instead, a tumor molecular profiling report from a College
of American Pathologists (CAP)/ Clinical Laboratory Improvements Amendments
(CLIA)-approved testing laboratory must be submitted for review by the Molecular
Review Committee (MRC)
• This molecular profiling must have been performed on a tumor sample that was
obtained at any point after initial tumor recurrence/progression and must be
accompanied by a pathology report for the same tumor specimen; a molecular
profiling report for a diagnostic (pre-treatment) tumor sample will be acceptable
for enrollment onto Pediatric MATCH only for children with high-grade gliomas of
the brainstem (diffuse intrinsic pontine gliomas) or thalamus. In the event that
molecular profiling reports are available from multiple timepoints, the most
recent report should be prioritized for study submission
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Karnofsky >= 50% for patients >
16 years of age and Lansky >= 50 for patients =< 16 years of age); note: neurologic
deficits in patients with central nervous system (CNS) tumors must have been stable
for at least 7 days prior to study enrollment; patients who are unable to walk because
of paralysis, but who are up in a wheelchair, will be considered ambulatory for the
purpose of assessing the performance score
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must have
radiographically measurable disease; measurable disease based on imaging obtained less
than or equal to 56 days prior to enrollment; patients with neuroblastoma who do not
have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable
disease are eligible; measurable disease in patients with CNS involvement is defined
as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance
imaging (MRI) or computed tomography (CT)
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression
post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: NOTE: patient does not need to meet all
subprotocol criteria at time of enrollment onto the APEC1621SC screening protocol, but
will need to meet all criteria prior to enrollment on any assigned treatment
subprotocol. Patients must be enrolled onto a subprotocol within 2 weeks (14 days) of
treatment assignment
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Karnofsky >= 50% for patients > 16 years
of age and Lansky >= 50 for patients =< 16 years of age); Note: neurologic deficits in
patients with CNS tumors must have been stable for at least 7 days prior to study
enrollment; patients who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the performance
score
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of treatment with subprotocol
specified therapy, the patients must have radiographically measurable disease;
patients with neuroblastoma who do not have measurable disease but have MIBG+
evaluable are eligible; measurable disease in patients with CNS involvement is defined
as any lesion that is at minimum 10 mm in one dimension on standard MRI or CT
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression
post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for
RECIST 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of enrollment onto a
subprotocol, the following general criteria for initiation of therapy will be
required:
• Patients must have fully recovered from the acute toxic effects of all prior
anticancer therapy and must meet the following minimum duration from prior
anticancer directed therapy prior to enrollment to the subprotocol; if after the
required timeframe, the numerical eligibility criteria are met, e.g. blood count
criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anticancer agents known to be
myelosuppressive: for agents not listed, the duration of this interval must
be discussed with the study chair and the study-assigned research
coordinator prior to enrollment >= 21 days after the last dose of cytotoxic
or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anticancer agents not known to be myelosuppressive (e.g. not associated with
reduced platelet or absolute neutrophil counts [ANC]): >= 7 days after the
last dose of agent; for agents not listed, the duration of this interval
must be discussed with the study chair and the study-assigned research
coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of
antibody, and toxicity related to prior antibody therapy must be recovered
to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth
factor; for agents that have known adverse events occurring beyond 7 days
after administration, this period must be extended beyond the time during
which adverse events are known to occur; the duration of this interval must
be discussed with the study chair and the study-assigned research
coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any
stem cell infusion including donor lymphocyte infusion (DLI) or boost
infusion: >= 84 days after infusion and no evidence of graft versus
host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular
therapy (e.g. modified T cells, natural killer (NK) cells, dendritic cells,
etc.)
• X-ray therapy (XRT)/External Beam Irradiation including Protons: >= 14 days
after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to
>= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM)
radiation; note: radiation may not be delivered to "measurable disease"
tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42
days after systemically administered radiopharmaceutical therapy
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: For patients with solid tumors without
known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients with known bone marrow
metastatic disease will be eligible for study provided they meet the blood counts (may
receive transfusions provided they are not known to be refractory to red cell or
platelet transfusions); these patients will not be evaluable for hematologic toxicity
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Creatinine clearance or radioisotope
glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on
age/gender as follows:
• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
• Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Bilirubin (sum of conjugated +
unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Serum glutamate pyruvate transaminase
(SGPT) (alanine transferase [ALT]) =< 135 U/L (for the purpose of this study, the ULN
for SGPT is 45 U/L)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients must be able to swallow intact
capsules/tablets, unless otherwise specified in the subprotocol to which they are
assigned
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Agent specific limitations on prior
therapy will be included with specific treatment subprotocols
Exclusion Criteria:
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Pregnant or breast-feeding women will not
be entered on this study due to risks of fetal and teratogenic adverse events as seen
in animal/human studies, or because there is currently no available information
regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in
females who are post-menarchal; males or females of reproductive potential may not
participate unless they have agreed to use an effective contraceptive method
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Concomitant medications
• Corticosteroids: at the time of consent and enrollment to regimen specific
subprotocols, patients receiving corticosteroids who have not been on a stable or
decreasing dose of corticosteroid for at least 7 days prior to enrollment to the
subprotocol will not be eligible; if used to modify immune adverse events related
to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: patients must meet criteria for prior therapy at the time
of consent and enrollment to a subprotocol; other investigational agents may not
be administered to patients while they are receiving study drug as part of a
subprotocol
• Anticancer agents: patients must meet criteria for prior therapy at the time of
consent and enrollment to a subprotocol; other investigational agents may not be
administered to patients while they are receiving study drug as part of a
subprotocol
• Anti-GVHD agents post-transplant: patients who are receiving cyclosporine,
tacrolimus or other agents to prevent graft-versus-host disease post bone marrow
transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have an uncontrolled
infection are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have had a prior solid organ
transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Additional agent specific criteria will
be included with specific treatment subprotocols
AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA)
Objectives
- Primary: To test the hypothesis that apixaban is superior to aspirin for the prevention
of recurrent stroke in patients with cryptogenic ischemic stroke and atrial cardiopathy.
- Secondary: To test the hypothesis that the relative efficacy of apixaban over aspirin
increases with the severity of atrial cardiopathy.
• Age ≥ 45 years.
• Clinical diagnosis of ischemic stroke + brain imaging to rule out hemorrhagic stroke.
• Modified Rankin Scale (MRS) score ≤ 4.
• Ability to be randomized within 3 to 180 days after stroke onset.
• ESUS, defined as all of the following:
• Stroke detected by CT or MRI that is not lacunar. Lacunar is defined as a
subcortical (this includes pons and midbrain) infarct in the distribution of the
small, penetrating cerebral arteries whose largest dimension is ≤1.5 cm on CT or
≤2.0 cm on MRI diffusion images/<1.5 cm on T2 weighted MR images. The following
are not considered lacunes: multiple simultaneous small deep infarcts, lateral
medullary infarcts, and cerebellar infarcts. Patients with a clinical lacunar
stroke syndrome and no infarct on imaging are excluded.
• Absence of extracranial or intracranial atherosclerosis causing ≥50 percent
luminal stenosis of the artery supplying the area of ischemia. Patients must
undergo vascular imaging of the extracranial and intracranial vessels using
either catheter angiography, CT angiogram (CTA), MR angiogram (MRA), or
ultrasound, as considered appropriate by the treating physician and local
principal investigator.
• No major-risk cardioembolic source of embolism, including intracardiac thrombus,
mechanical prosthetic cardiac valve, atrial myxoma or other cardiac tumors,
moderate or severe mitral stenosis, myocardial infarction within the last 4
weeks, left ventricular ejection fraction <30 percent, valvular vegetations, or
infective endocarditis). Patent foramen ovale is not an exclusion. All patients
must undergo electrocardiogram, transthoracic or transesophageal echocardiography
(TTE or TEE) and at least 24 hours of cardiac rhythm monitoring (Holter monitor
or telemetry or equivalent). Additional cardiac imaging, such as cardiac MRI, or
cardiac CT will be performed at the discretion of the local treating physician
and principal investigator. Additional cardiac rhythm monitoring, such as
monitored cardiac outpatient telemetry (MCOT) or an implanted cardiac monitor,
will be at the discretion of the treating physician and local principal
investigator.
• No other specific cause of stroke identified, such as arteritis, dissection,
migraine, vasospasm, drug abuse, or hypercoagulability. Special testing, such as
toxicological screens, serological testing for syphilis, and tests for
hypercoagulability, will be performed at the discretion of the treating physician
and local principal investigator.
Exclusion Criteria:
• History of atrial fibrillation (AF), AF on 12-lead ECG, or any AF of any duration
during heart-rhythm monitoring prior to randomization.
• Clear indication for treatment-dose anticoagulant therapy, such as venous
thromboembolism or a mechanical heart valve.
• Need for antiplatelet agent, such as aspirin or clopidogrel
• History of spontaneous intracranial hemorrhage.
• Chronic kidney disease with serum creatinine ≥2.5 mg/dL.For Canadian sites only,
estimated creatinine clearance (eCrCl) <15 mL/min is also an exclusion criterion.
• Active hepatitis or hepatic insufficiency with Child-Pugh score B or C.
• Clinically significant bleeding diathesis.
• Unresolved anemia (hemoglobin <9 g/dL) or thrombocytopenia (<100 x 10E9/L).
• Clinically significant gastrointestinal bleeding within the past year (e.g., not due
to external hemorrhoids).
• At risk for pregnancy: premenopausal or postmenopausal woman within 12 months of last
menses without a negative pregnancy test or not committing to adequate birth control,
which includes an oral contraceptive, two methods of barrier birth control such as
condom with or without spermicidal lubricant + diaphragm, or abstinence.
• Known allergy or intolerance to aspirin or apixaban.
• Concomitant participation in another clinical trial involving a drug or acute stroke
intervention.
• Considered by the investigator to have a condition that precludes follow-up or safe
participation in the trial.
• Inability of either participant or surrogate to provide written, informed consent for
trial participation.
Exploring the Effects of Corticosteroids on the Human Hippocampus
Chronic corticosteroid (CS) exposure is associated with changes in memory and the hippocampus
in both humans and in animal models. The hippocampus has a high concentration of
glucocorticoid receptors (GCRs), and the pre-clinical literature demonstrates shortening of
apical dendrites in the CA3 region of the hippocampus and decreased neurogenesis in the
dentate gyrus (DG) following CS administration. In humans, both stress and CS exposure are
associated with a decline in declarative memory performance (a process mediated by the
hippocampus). Impairment in declarative memory and hippocampal atrophy are reported in
patients with excessive CS release due to Cushing's disease, and, by our group, in patients
receiving prescription CS therapy. These findings have important implications for patients
with mood disorders, as a large subset of people with major depressive disorder (MDD) show
evidence of HPA axis activation, elevated cortisol and, importantly, resistance to the
effects of CSs on both the HPA axis and on declarative memory. Thus, resistance to
corticosteroids appears to be a consequence of MDD.
this study will examine changes in declarative memory, as well as use state-of-the-art
high-resolution multimodal neuroimaging, including structural and functional (i.e.,
task-based and resting state) MRI, in both men and women healthy controls, and, as an
exploratory aim, a depressed group, given 3-day exposures to hydrocortisone (160 mg/day) or
placebo. The study will translate preclinical findings to humans, provide valuable data on
possible sex differences in the response to cortisol and, for the first time, identify
specific hippocampal subfields (e.g., CA3/DG) in humans that are most sensitive to acute CS
effects. Using resting state fMRI data and whole brain connectomics using graph theoretical
approaches, we will determine the effects of cortisol exposure on functional brain networks.
Furthermore, this will be the first study to use neuroimaging to compare the brain's response
to CSs in people with depression vs. controls, and determine whether depressed people
demonstrate glucocorticoid resistance within the hippocampus. We hypothesize that hippocampal
response to acute CSs will be greatest in the CA3/DG subfield, greater in women than in men,
and that depressed people will show a blunted hippocampal response to CSs compared to
controls. A multidisciplinary research team with extensive experience in CS effects on the
brain and hippocampal subfield neuroimaging, and a prior history of research collaboration,
will conduct the project.
• Men and women age 18-40 years with vision corrected to at least 20-40 (needed for fMRI
tasks)
• Education of ≥ 12 years
• Baseline RAVLT total words recalled T-score ≥ 40 (normal range)
• BMI between 18.5-35.0 (neither underweight nor severely obese)
• Baseline QIDS-C ≤ 5 (virtual absence of depressive symptoms) for "healthy controls"
and for the "depressed" group a QIDS-C between 11-20 (≥ moderate depressive symptoms
but < very severe depressive symptoms)
Exclusion Criteria:
• History of major psychiatric illness other than MDD for the depressed group, defined
as bipolar disorder, posttraumatic stress disorder, schizoaffective disorder,
schizophrenia, eating disorders, or MDD with psychotic features. For the control
group, a past episode of MDD (per SCID) is also exclusionary
• History of drug or alcohol use disorder
• History of neurological disorders including seizures, brain surgery, multiple
sclerosis, Parkinson's disease
• Taking CNS-acting medications (e.g., antidepressants, antipsychotics, lithium,
anticonvulsants, sedative/hypnotic/anxiolytics). Thus, the depressed group will be
medication free.
• History of allergic reaction or medical contraindication to hydrocortisone
• Metal implants, claustrophobia, or other contraindications to MRI
• Significant medical conditions (e.g., cancer, heart disease, diabetes)
• Vulnerable population including pregnant or nursing women, prisoners, and people with
intellectual disability, history of special education classes, dementia, or other
severe cognitive disorders
• Current suicidal ideation, a suicide attempt in the past 12 months or more than one
lifetime attempt
• History of systemic CS use in the past 12 months, lifetime cumulative use of more than
12 weeks, or recent (defined as past 28 days) inhaled CS use
• Women who are using estrogen containing oral contraceptive agents (other
contraceptives are acceptable, see Protection of Human Subjects section for a list of
acceptable birth control methods) or who are post- or peri-menopausal or with
irregular menstrual cycles (i.e., inconsistent menstruation patterns)
Evaluation of [18F]FLT PET/CT as an Early Predictor of Outcome in Pediatric Solid Tumors
The experimental [18F]FLT-PET/CT will be completed before initiation of chemotherapy at
either diagnosis or initiation of salvage chemotherapy at relapse and prior to the third
cycle (or month) of chemotherapy. Laboratory analysis and correlative radiology, as directed
per clinical care based on the primary diagnosis, are required within 30 days of the baseline
[18F]FLT PET/CT. Follow-up will comprise 24 months of standard practice treatment and follow
up.
• Patients with histologically confirmed solid tumor malignancies with residual tumors
present that require standard of care chemotherapy for a minimum number of cycles. All
anatomical sites and all tumor histologies are eligible including central nervous
system tumors. Both newly diagnosed and/or newly relapsed patients are eligible.
• Patients ages 8 •25 years
• In the opinion of the investigator, patients must be thought to be able to lie still
for imaging without sedation for 20 •30 minutes.
• Patients must have a performance status of > 50% (Lansky or Karnofsky).
• Patients of childbearing potential must have a negative urine or serum pregnancy test
as per institution's standard of care within 7 days prior to [18F]FLT PET/CT imaging.
• Ability to understand and the willingness to sign a written informed consent/assent.
Exclusion Criteria:
• Patients with known allergic or hypersensitivity reactions to previously administered
radiopharmaceuticals of similar chemical or biologic composition to [18F]FLT
• Newly diagnosed subjects who had prior chemotherapy or radiotherapy before enrollment
in the study. Relapsed patients are eligible prior to starting their relapsed
chemotherapy regimen if they meet the other eligibility criteria.
• Subjects for whom chemotherapy is not a standard of care primary therapy option.
• Patients who are pregnant or breast-feeding.
• Patients with no residual tumor (i.e. complete resection at diagnosis or relapse).
Drug: [18F]FLT-PET/CT
Sarcoma, Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, Breast - Female, Breast - Male, Carcinoid Tumor, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Small Intestine, Soft Tissue
A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors (LIBRETTO-121)
This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric
participants with an activating rearranged during transfection (RET) alteration and an
advanced solid or primary CNS tumor.
• Advanced or metastatic solid or primary CNS tumor which has failed standard of care
therapies
• Evidence of an activating RET gene alteration in the tumor and/or blood
• Measurable or non-measurable disease
• Karnofsky (participants 16 years and older) or Lansky (participants younger than 16)
performance score of at least 50
• Participant with primary CNS tumors or cerebral metastases must be neurologically
stable for 7 days prior and must not have required increasing doses of steroids within
the last 7 days
• Adequate hematologic, hepatic and renal function.
• Ability to receive study drug therapy orally or via gastric access
• Willingness of men and women of reproductive potential to observe conventional and
effective birth control
Exclusion Criteria:
• Major surgery within two weeks prior to planned start of LOXO-292
• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of
myocardial infarction within 6 months prior to planned start of LOXO-292
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection
• Clinically significant active malabsorption syndrome
• Pregnancy or lactation
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant
required a modification to current thyroid medication in the 7 days before start of
LOXO-292)
• Uncontrolled symptomatic hypercalcemia or hypocalcemia
• Known hypersensitivity to any of the components of the investigational agent, LOXO-292
or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension
• Prior treatment with a selective RET inhibitor(s) (including investigational selective
RET inhibitor[s])
Cladribine Tablets: Collaborative Study to Evaluate Impact On Central Nervous System Biomarkers in Multiple Sclerosis (CLOCK-MS)
The purpose of this study is to better understand the mechanism of action (MoA) of cladribine
tablets by exploring the effect on central nervous system (CNS) and blood biomarkers relevant
in the relapsing forms of multiple sclerosis (RMS; to include relapsing-remitting MS [RRMS]
or active secondary progressive MS).
1. Have a relapsing form of multiple sclerosis (RMS; to include RRMS or active secondary
progressive MS)
2. Are willing and able to receive at least 2 lumbar punctures
3. Have an EDSS of 0 to ≤ 5.5 during the screening period
4. Had at least 1 relapse or 1 gadolinium-enhancing or 1 new or enlarged T2 lesion in the
last 12 months
5. Have absolute lymphocyte count (ALC) within normal range of the local laboratory or
assessed as normal by the investigator within the 3 week screening period and meet all
other eligibility criteria for cladribine tablet treatment
6. Capable of giving signed informed consent
Exclusion Criteria:
1. Have any contraindication for lumbar puncture
2. Have current malignancy
3. Are infected with human immunodeficiency virus (HIV)
4. Have active chronic infections (e.g. hepatitis or tuberculosis)
5. Have signs or symptoms suggestive of progressive multifocal leukoencephalopathy (PML)
in MRI
6. Have history of hypersensitivity to cladribine or any of the excipients listed in the
cladribine tablets US Prescribing Information
7. Allergy or hypersensitivity to gadolinium and/or any other contraindication to perform
a MRI
8. Have any other comorbid conditions that preclude participation
9. Have been previously treated with cladribine
10. Have previously been treated with ocrelizumab, alemtuzumab, rituximab, or daclizumab
11. Have received treatment with natalizumab during the last 6 months
12. Are currently receiving immunosuppressive or myelosuppressive therapy, e.g.,
methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic treatment
with systemic corticosteroids
13. Have received treatment with immunosuppressive or myelosuppressive therapy during the
last 6 months
14. Have received chronic treatment with systemic corticosteroids during the last 4 weeks
15. Have moderate or severe hepatic impairment (Child-Pugh score >6)
16. Have moderate or severe renal impairment (creatinine clearance <60 mL per minute)
17. Are pregnant or unwilling or unable to use effective contraception during cladribine
tablets dosing and for 6 months after the last dose in each treatment course
18. Are intending to breastfeed on a cladribine tablet treatment day and/or during the 10
days after the last cladribine tablet dose.
Antipsychotic Response to Clozapine in B-SNIP Biotype-1 (Clozapine)
The CLOZAPINE study is designed as a multisite study across 5 sites and is a clinical trial,
involving human participants who are prospectively assigned to an intervention. The study
will utilize a stringent randomized, double-blinded, parallel group clinical trial design. B2
group will serve as psychosis control with risperidone as medication control. The study is
designed to evaluate effect of clozapine on the B1 participants, and the effect that will be
evaluated is a biomedical outcome. The study sample will be comprised of individuals with
psychosis, including 1) schizophrenia, 2) schizoaffective disorder and 3) psychotic bipolar I
disorder. The investigators plan to initially screen and recruit n=524 (from both the
existing B-SNIP library and newly-identified psychosis cases, ~50% each) in order to enroll
n=320 (B1 and B2) into the RCT.
• 18-60y/o; males and females; all races and ethnicities; able to provide written
informed consent; able to read, speak, and understand English; medically stable;
meeting DSM-IV (SCID-based) criteria for schizophrenia, schizoaffective disorder, or
bipolar I disorder with psychotic features (we will use DSM-IV to be consistent with
prior B-SNIP samples); PANSS total score of ≥70 and at least one item scored ≥5 or two
items scored ≥4 on PANSS Positive Subscale; normal baseline values for absolute
neutrophil count (ANC above 1500/mm3)
Exclusion Criteria:
• premorbid intellectual ability estimate below 70 (WRAT-4, Word Reading subtest,
age-corrected standardized score); comorbid DSM-IV diagnosis of alcohol or substance
abuse in prior 1 month or substance dependence in prior 3 months; neurological (e.g.,
seizure disorder, stroke, traumatic brain injury with a loss of consciousness ≥ 30min)
or severe medical condition (e.g., decompensated cardiovascular disorder, AIDS) that
may affect central nervous system function; concomitant medications known to affect
EEG properties (i.e., lithium, anticonvulsants, benzodiazepines) or strong CYP 1A2
inhibitors (e.g., ciprofloxacin, enoxacin) or strong CYP 3A4 inducers (e.g.,
phenytoin, carbamazepine, phenobarbital, rifampin) which cannot be safely
discontinued; vulnerable populations (e.g., pregnant, nursing, incarcerated);
unwilling to use reliable means of contraception; history of neuroleptic malignant
syndrome; prior treatment with clozapine, prior treatment with long-acting injectable
antipsychotics that are 1-month formulations within the past 3 months and for 3-month
formulations within the past 6 months; intolerable side effects to either clozapine or
risperidone in lifetime, or a previously failed trial of either clozapine or
risperidone at adequate doses in lifetime; history of drug reaction with eosinophilia
and systemic symptoms syndrome (DRESS), also known as drug-induced hypersensitivity
syndrome (DIHS); high risk for suicide defined as more than 1 attempt in past 12
months that required medical attention, any attempt in the past 3 months or current
suicidal ideation with plan and intent such that outpatient care is precluded; current
homicidal ideation with plan and intent such that outpatient care is precluded.
Drug: clozapine, Drug: risperidone
Schizophrenia, Schizoaffective Disorder, Brain and Nervous System, Bipolar 1 Disorder
TReatment for ImmUne Mediated PathopHysiology (TRIUMPH)
TReatment for ImmUne Mediated PathopHysiology (TRIUMPH) is a multi-center, three arm,
randomized, controlled trial of immunosuppressive therapy for children with acute liver
failure. The study will determine if suppressing inflammatory responses with either
corticosteroids or equine anti-thymocyte globulin therapy improves survival for children with
this rare, life-threatening condition.
1. Patient with liver injury of ≤ 6 weeks duration resulting in an international
normalized ratio (INR) of ≥ 1.5 and < 2.0 (not corrected by vitamin K) with evidence
of hepatic encephalopathy (HE) or INR ≥ 2.0 without evidence of HE.
2. Age is greater than or equal to 1 year and less than 18 years of age.
3. Patient or their legally authorized representative(s) (LAR) must consent (and assent,
if applicable) to be in the study and must have signed and dated an approved informed
consent form which conforms to federal and institutional guidelines.
4. Females of reproductive potential should not plan on conceiving children during the
study and must agree to use a medically accepted form of contraception.
Exclusion Criteria:
1. Evidence of active infection with Hepatitis A, B, C, E or evidence of acute herpes
simplex virus (HSV) or adenovirus infection
2. Travel within the past 3 months to an area highly endemic for Hepatitis E
3. Diagnosis of hemophagocytic lymphohistiocytosis (HLH) Note: Patients with a history of
consanguinity and/or central nervous system (CNS) dysfunction that is exaggerated
compared to the degree of liver dysfunction (as judged by the site investigator) will
not be enrolled until results of rapid genetic testing are available. Turn-around time
for genetic testing results is estimated to be 72-96 hours.
4. Aplastic anemia as defined by standardized criteria [1] diagnosed prior to enrollment
5. Diagnosis of autoimmune Hepatitis (AIH)
6. Diagnosis of acute Wilson disease
7. Diagnosis of inborn error of metabolism Note: Suspicion of metabolic disease is not an
exclusion for entry into the Trial.
8. Diagnosis of acute drug or toxin-induced liver injury
9. History of recreational drug use within the past 4 weeks
10. Therapy with an immunosuppressive agent, including chemotherapy, biological therapies
or an experimental drug or device within the past 6 weeks
11. Liver injury due to ischemia
12. Liver dysfunction diagnosed more than 6 weeks prior to screening
13. History of allergy to horse dander
14. Sepsis
15. Imminent risk of death as judged by the clinical site investigator, including but not
limited to; signs of cerebral herniation at the time of enrollment and presence of
intractable arterial hypotension
16. Solid organ or stem cell transplant recipient
17. Pregnant or breast-feeding at the time of proposed study entry
18. Clinical AIDS or HIV positive
19. History of any form of malignant neoplasm and/or tumors treated within five years
prior to study entry (other than non-melanoma skin cancer or in situ cervical cancer)
or where there is current evidence of recurrent or metastatic disease
20. Received a live-virus vaccine within 4 weeks of study entry
21. Positive test result for the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection
22. Psychiatric or addictive disorders that would preclude obtaining informed
consent/assent
23. Patient is unwilling or unable to adhere with study requirements and procedures
24. Currently receiving other experimental therapies
The Symptomatic Cerebral Cavernous Malformation Trial of REC-994 (SYCAMORE)
This is a multi-center, randomized, double-blind, placebo-controlled study to investigate the
safety, efficacy and pharmacokinetics of REC-994 (200 mg and 400 mg) compared to placebo in
subjects with symptomatic cerebral cavernous malformation (CCM).
Inclusion criteria:
1. 18 years of age or older with anatomic CCM lesions demonstrated by brain MRI
2. Have symptomatic CCM
3. Have provided written informed consent to participate in the study
4. Have NOT participated in a clinical trial utilizing an investigational agent within 28
days or within 6 half-lives of the investigational drug (whichever is longer) prior to
Screening
Exclusion Criteria:
1. Symptoms deemed by the study Investigator to be caused exclusively by irreversible
neuronal damage from prior stroke or neurosurgical instrumentation
2. History of cranial irradiation or surgical/radiosurgical treatment of the primary
symptomatic CCM lesion
3. Pregnant or breast feeding
4. Be unable or unwilling to participate in MRI assessments (eg, claustrophobia, metal
implant or implanted cardiac pacemaker)
5. Liver dysfunction or active liver disease as defined by baseline serum transaminases
>2x upper limit of normal (ULN)
6. Have severely impaired renal function (eGFR <60ml/min) or active renal disease
7. Have had a previous diagnosis of skeletal muscle disorders (myopathy) of any cause or
have a baseline creatine kinase level > 5x ULN
8. History of alcohol or substance abuse within 1 year prior to screening
9. Clinically significant laboratory abnormality
10. Have had an intracerebral hemorrhage within 3 months of screening or any brain surgery
within 6 months of screening
Impact of Intensive Treatment of SBP on Brain Perfusion, Amyloid, and Tau (IPAT Study) (IPAT)
The purpose of this study is to determine if intensive lowering of systolic blood pressure
(SBP), using FDA approved medications (antihypertensive), reduces Alzheimer's Disease
pathology (i.e., excessive brain amyloid and tau protein deposition) in older adults at high
risk for memory decline or dementia.
• Age 60-80, all races/ethnicities, and both sexes are eligible;
• a) A positive family history of dementia defined as having at least one first-degree
relative with a history of AD or other type of dementia or
• b) having subjective memory complaints defined as a positive answer to BOTH of the
following questions:
1. "Are you worried about your memory or thinking abilities?
a) Not at all, b) A little bit, c) A lot"; B and C •includes
2. "Do you feel you have difficulty with your memory or thinking that is worse than
in the past?" b) Yes or No; Yes •includes
• Mini-Mental State Exam (MMSE) ≥ 26 to exclude gross dementia; based on clinical
judgment, may be rescreened in ≥ 7 days;
• Individuals with SBP ≥ 130 and SBP ≤ 180; Those on antihypertensives are eligible. If
an individual, not treated for HTN, has a SBP ≥ 125 mmHg, consider rescreening after
24 hours;
• Willingness to be randomized into the treatment groups and ability to return to clinic
for follow-up visits over 24 months;
• Fluency in English or Spanish or both, adequate visual and auditory acuity to allow
neuropsychological testing;
• Participants must have a regular healthcare provider.
Exclusion Criteria:
• Clinically documented history of stroke, focal neurological signs or other major
cerebrovascular diseases based on clinical judgment or MRI/CT scans such as evidence
of infection, infarction, or other brain lesions;
• Diagnosis of AD or other type of dementia, or significant neurologic diseases such as
Parkinson's disease, seizure disorder, multiple sclerosis, history of severe head
trauma or normal pressure hydrocephalus;
• Evidence of severe major depression (GDS ≥ 12, may be rescreened after 12 weeks or
longer if evidence of reactive depression or temporary mood disturbances) or
clinically significant psychopathology, (e.g., psychosis and schizophrenia); if
hospitalized in past year, can be rescreened in 6 months; or presence of a major
psychiatric disorder that in the investigator's opinion, could interfere with
adherence to research assessments or procedures.
• Unstable heart disease based on clinical judgment (e.g., heart attack/cardiac arrest,
cardiac bypass procedures within previous 6 months and congestive heart failure), or
other severe medical conditions;
• History of atrial fibrillation and evidence on ECG with any of the following: active
symptoms of persistent palpitation, dizziness, history of syncope, chest pain,
dyspnea, orthopnea, shortness of breath at rest, or paroxysmal nocturnal dyspnea
within the past 6 months; resting heart rate of < 30 or > 110 bpm; taking class I or
III antiarrhythmic drugs including flecainide, propafenone, dronedarone, sotalol,
dofetilide, and amiodarone; or clinical concerns for safely participating in lowering
blood pressure.
• Systolic BP equal or greater than 180 mmHg and/or diastolic BP equal or greater than
110 mmHg, may be rescreened in 1 week.
• Orthostatic hypotension, defined as the third standing SBP < 100mmHg, may be
rescreened after 2 weeks;
• History of significant autoimmune disorders such as systemic lupus erythematosus,
rheumatoid arthritis or polymyalgia rheumatica;
• Significant history of alcoholism or drug abuse within the last five years;
• Uncontrolled diabetes mellitus, defined as hemoglobin A1C > 6.5%, or requiring insulin
treatment;
• Clinically diagnosed and untreated sleep apnea;
• Regularly smoking cigarettes within the past year;
• Pacemaker or other medical device of metal that precludes performing MRI;
• Women with a potential for pregnancy, lactation/childbearing (2 year post-menopausal
or surgically sterile to be considered not childbearing potential);
• Participant enrolled in another investigational drug or device study, either currently
or within the past 2 months;
• Severe obesity with BMI > 40 ; clinical judgment should be applied in all cases to
assess patient safety and anticipated compliance;
• Allergy to angiotensin receptor blockers (ARBs), i.e., drugs that have a suffix
"-sartan"; allergy to amlodipine;
• Abnormal screening laboratory tests (e.g., liver ALT and AST > 3 x ULN, GFR < 30 or
Hct < 28%); may be rescreened after 2 weeks or longer;
• A medical condition likely to limit survival to less than 3 years;
• Participant has any condition(s) judged by the study investigator to be medically
inappropriate, risky or likely to cause poor study compliance. For example:
1. Plans to move outside the clinic catchment area in the next 2 years;
2. Significant concerns about participation in the study from spouse, significant
other, or family members;
3. Lack of support from primary health care provider;
4. Residence too far from the study clinic site such that transportation is a
barrier including persons who require transportation assistance provided by the
study clinic funds for screening or randomization visits;
5. Residence in a nursing home; persons residing in an assisted living or retirement
community are eligible if they meet the other criteria;
6. Other medical, psychiatric, or behavioral factors that, in the judgment of the
site PI or clinician, may interfere with study participation or the ability to
follow the study Protocol.
7. Couples or significant partners who live together cannot be enrolled or
participate simultaneously in the study.
Drug: Angiotensin II Receptor Blockers (ARBs, losartan) and Calcium Channel Blockers (CCB, amlodipine), Other: PCP
Hypertension, Cognitively Normal Older Adults, Subjective Cognitive Decline, Brain and Nervous System, Family History of Dementia
Dementia, Alzheimer's Disease, Cognitive Function, Blood Pressure, Amyloid, Tau
Pediatric Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (P-ICECAP) (ICECAP)
This is a multicenter trial to establish the efficacy of cooling and the optimal duration of
induced hypothermia for neuroprotection in pediatric comatose survivors of cardiac arrest.
The study team hypothesizes that longer durations of cooling may improve either the
proportion of children that attain a good neurobehavioral recovery or may result in better
recovery among the proportion already categorized as having a good outcome.
Inclusion criteria:
• Age 2 days to < 18 years with corrected gestational age of at least 38 weeks
• Chest compressions for at least 2 minutes
• Coma or encephalopathy after resuscitation from Out-of-Hospital Cardiac Arrest (OHCA)
• Requires continuous mechanical ventilation through endotracheal tube or tracheostomy
• Definitive temperature control device initiated
• Randomization within 6 hours of Return of Spontaneous Circulation (ROSC)
• Informed consent from Legally Authorized Representative (LAR) including intent to
maintain life support for 120 hours
Exclusion criteria:
• Glasgow Coma Motor Score (GCMS) = 6
• LAR does not speak English or Spanish
• Duration of Cardiopulmonary Resuscitation (CPR) > 60 minutes
• Severe hemodynamic instability with continuous infusion of epinephrine or
norepinephrine of 2 micrograms per kilogram per minute (μg/kg/minute) or initiation of
Extracorporeal membrane oxygenation (ECMO)
• Pre-existing severe neurodevelopmental deficits with Pediatric Cerebral Performance
Category (PCPC) =5 or progressive degenerative encephalopathy
• Pre-existing terminal illness, unlikely to survive to one year
• Cardiac arrest associated with brain, thoracic, or abdominal trauma
• Active and refractory severe bleeding prior to randomization
• Extensive burns or skin lesions incompatible with surface cooling
• Planned early withdrawal of life support before 120 hours
• Sickle cell anemia
• Pre-existing cryoglobulinemia
• Non-fatal drowning in ice covered water
• Central nervous system tumor with ongoing chemotherapy
• Previous enrollment in P-ICECAP trial
• Prisoner
• Chronic hypothermia
• New post-cardiac arrest diabetes insipidus
• Pregnancy
A Prospective, Multi-center, Randomized Controlled Blinded Trial Demonstrating the Safety and Effectiveness of VNS Therapy® System as Adjunctive Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression (RECOVER)
Objectives of this study are to determine whether active VNS Therapy treatment is superior to
a no stimulation control in producing a reduction in baseline depressive symptom severity,
based on multiple depression scale assessment tools at 12 months from randomization.
The patient must be in a major depressive disorder (MDD) episode for ≥ two years or have
had at least four episodes of MDD, including the current episode.
The patient's depressive illness meets a minimum criterion of four prior failed treatments
of adequate dose and duration as measured by a tool designed for this purpose.
The patient is experiencing a major depressive episode (MDE) as measured by a guideline
recommended depression scale assessment tool on two visits, within a 45-day span prior to
implantation of the VNS device.
Patients must maintain a stable medication regimen for at least four weeks before device
implantation.
Exclusion Criteria:
Current or lifetime history of psychotic features in any MDE;
Current or lifetime history of schizophrenia or schizoaffective disorder;
Current or lifetime history of any other psychotic disorder;
Current or lifetime history of rapid cycling bipolar disorder;
Current secondary diagnosis of delirium, dementia, amnesia, or other cognitive disorder;
Current suicidal intent; or
Treatment with another investigational device or investigational drugs.
Device: Vagus Nerve Stimulation (VNS)
Treatment Resistant Depression, Brain and Nervous System